We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD]neg) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel-treated patients achieving MRDneg. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRDneg. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRDneg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Introduction:CAR T-cell therapies have revolutionized treatment for relapsed/refractory (R/R) DLBCL; however, high rates of progression and relapse have been observed, and their widespread use is limited by high toxicity rates, long vein-to-vein (VTV) times, and limited access. Anti-CD19 CAR T-cell therapies offering short VTV times and preservation of early phenotype can improve efficacy and safety outcomes in patients (pts) with aggressive lymphomas. Here, we present updated results for pts with R/R DLBCL from the ATALANTA-1 study of GLPG5101, a fresh, early memory-enriched phenotype autologous CD19 CAR T-cell therapy manufactured using a decentralized cell therapy platform. Methods: ATALANTA-1 (CTIS: 2022-502661-23-00; NCT06561425) is a Phase 1/2 study of GLPG5101 in pts with R/R non-Hodgkin lymphoma. Pts who were refractory or relapsed after ≥1 lines of therapy were enrolled. Primary objectives were safety and establishment of the recommended Phase 2 dose in Phase 1, and efficacy in Phase 2. Safety, pharmacokinetics, T-cell phenotypes, and efficacy data pooled across planned dose levels (DLs) are reported for pts with R/R DLBCL: DL1, 35–50×106; DL2, 85–110×106; DL3, 200–250×106CAR T cells. Results: As of 21 April 2025, 24 pts with DLBCL underwent leukapheresis; 1 pt discontinued before lymphodepletion: a dropout rate of 1/24 (4%). Decentralized manufacturing enabled all 23 pts to receive a fresh product with a median (range) VTV time of 7 (7–21) days. None of the pts required bridging chemotherapy. In the efficacy analysis set (EAS, n=22), median (range) pt age was 69 (25–79) years; 5/22 (23%) pts had high-risk International Prognostic Index scores at study entry and 16/22 (73%) had intermediate risk. 20/22 (91%) pts had Ann Arbor disease Stage III–IV; 4/22 (18%) had MYC and BCL2 and/or BCL6 rearrangements (double/triple hit); 12/22 (55%) were refractory to the last line of therapy. Median (range) number of prior systemic lines of therapy was 1 (1–6), and 10/22 (45%) pts received GLPG5101 CAR T-cell therapy in the third or later line (3L+) setting. Among 12 pts infused in 2L, 8 (67%) were primary refractory. During the treatment period (≤14 weeks post-infusion), most Grade (G) ≥3 treatment-emergent adverse events (TEAEs) were hematologic. CRS was reported in 41% (9/22) of pts, all G1/G2 apart from a single G3 event. ICANS was reported in 27% (6/22) of pts, all G1 apart from a single G3 event. There were 7 deaths: 3 due to progressive disease, 2 considered attributable to TEAEs during the treatment period (intracranial hemorrhage, n=1; intra-abdominal hemorrhage, n=1), and 2 considered attributable to AEs during the follow-up period (hemophagocytic lymphohistiocytosis due to a second primary malignancy, 22.9 months post-infusion while in complete response [CR], n=1; COVID-19, n=1). At data cutoff, median (95% CI) follow-up duration was 15.1 (4.6, 23.2) months. The objective response rate (ORR) was 75% (18/24) in the intention-to-treat population and 82% (18/22) in the EAS. The CR rate (CRR) was 58% and 64%, respectively. Notably, for 3L+ pts, the ORR was 90% (9/10), with a CRR of 80% (8/10). The Kaplan–Meier (KM)-estimated 12-month duration of response (DOR) rate for the overall and 3L+ pt population was 50% and 63%, respectively. Compared with the starting material, the proportion of early memory phenotype CD8+CAR T cells increased significantly in the final product, and increased moderately within CD4+ CAR T cells, in 89% (17/19) of evaluable pts. These increases drove a corresponding reduction of terminally differentiated effectors. CAR T cells were detected in peripheral blood in >50% of evaluated pts until ≥18 months post-infusion. Conclusions: GLPG5101, a CAR T-cell product with an early memory-enriched T-cell phenotype, demonstrated encouragingly high clinical activity and a favorable safety profile, as well as long-term persistence, in pts with R/R DLBCL. Decentralized manufacturing resulted in a fresh product infusion in all pts, with a median VTV time of 7 days, and a low dropout rate (4%). Among 3L+ pts (n=10), the ORR and CRR were 90% and 80% respectively, with a KM-estimated 12-month DOR of 63%. High-grade toxicities were infrequent, with only 1 case each of G3 CRS and ICANS. These results suggest GLPG5101 addresses current unmet needs of durable efficacy, low toxicity, and rapid VTV time, and thus support continued development of GLPG5101 for pts with R/R DLBCL.

Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. TRANSFORM (NCT03575351) is a global, randomized, open-label, phase 3 study of liso-cel versus SOC as second-line therapy in adults with R/R LBCL. In the TRANSFORM study, liso-cel showed superior, more durable efficacy versus SOC, with a potential long-term survival benefit and a favorable safety profile, highlighting the curative potential of liso-cel for second-line R/R LBCL. Upon completion of TRANSFORM, patients who received liso-cel could enroll into a separate, long-term follow-up (LTFU) study (NCT03435796). Here, we report results after approximately 4 years of follow-up in patients from TRANSFORM who consented to the LTFU study. The TRANSFORM study compared liso-cel versus SOC (chemotherapy [R-DHAP, R-ICE, or R-GDP] followed by high-dose chemotherapy [HDCT] + ASCT) in adults aged ≤ 75 years with LBCL primary refractory to or relapsed within 12 months of first-line therapy and eligible for ASCT. Patients in the liso-cel arm underwent lymphodepletion followed by liso-cel (100 × 106 CAR+ T cells). Crossover to receive liso-cel was allowed for patients in the SOC arm. The LTFU study enrolled patients who received liso-cel and discontinued early or completed TRANSFORM; liso-cel was not administered during the LTFU study and subsequent therapies were administered at investigator discretion. Selected AEs considered related to liso-cel (malignancies, neurologic, hematologic, or rheumatologic/autoimmune disorders) and OS would be assessed at each visit (month 3 and then every 6 months from years 1 to 5, and then annually) for up to 15 years from liso-cel infusion until study withdrawal or death, whichever occurred first. OS for the combined study was defined as the time from randomization to death due to any cause. PFS for the combined TRANSFORM and LTFU studies incorporated data from TRANSFORM, assessed by an independent review committee, and from LTFU, assessed by investigators, and was defined as the time from randomization to disease progression or death from any cause. For LTFU only, OS and PFS were measured from LTFU consent to event or censoring. In cases where the patient was censored at last assessment date (without receiving new therapy) in TRANSFORM and enrolled in LTFU, LTFU data were used. For patients from the liso-cel arm of TRANSFORM who did not enroll in the LTFU study, the data from TRANSFORM were considered (ie, either an event or censored) at their last adequate assessment date or before starting new therapy. Results are reported descriptively. In total, 184 patients were randomized in TRANSFORM (92 per arm); key demographics and baseline characteristics were previously reported (Abramson, et al. Blood 2023). The LTFU study enrolled 67 patients who received liso-cel (liso-cel arm, n = 43; crossover from SOC arm, n = 24). The median follow-up (range) for the liso-cel arm was 16.9 months (1.3–29.7) in the LTFU study and 40.1 months (2.2–61.9) combining the TRANSFORM and LTFU studies. The median follow-ups for OS and PFS for the liso-cel arm in the LTFU study were 17.1 (16.1–21.9) and 16.9 months (16.0–21.8), respectively. In patients from the LTFU study in the liso-cel arm (n = 43), median PFS and OS were both not reached (NR) with 95% CIs of NR–NR. The 24-month rates (95% CI) of PFS and OS were 94.7% (87.4–100.0) and 95.1% (88.4–100.0), respectively. In the 92 patients randomized to the liso-cel arm, using combined data from the TRANSFORM and LTFU studies, median (95% CI) PFS was NR (12.6–NR); 48-month PFS rate was 52.2% (41.5–62.8). Median (95% CI) OS was NR (NR–NR); 48-month OS rate was 61.5% (51.2–71.7). Safety results from the LTFU study in the liso-cel arm showed no new signals compared with previous reports from TRANSFORM. AEs of any grade occurred in 2 patients (hypogammaglobulinemia and dyspnea; n = 1 each), with no second primary malignancies or serious infections. AEs of grade 3 or 4 occurred in 1 patient (dyspnea). No AEs led to death.Conclusions: After a median follow-up of approximately 4 years combining data from the TRANSFORM and LTFU studies, liso-cel continued to demonstrate long-term clinical benefit with high PFS and OS rates in patients with second-line R/R LBCL. The safety profile of liso-cel continued to be manageable with no new safety signals observed during LTFU. These results further support liso-cel as an effective second-line treatment with curative potential for R/R LBCL.

We report 3-year follow-up results from TRANSFORM comparing lisocabtagene maraleucel (liso-cel) versus standard of care (SOC) for second-line primary refractory/early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (N = 184) were randomly assigned 1:1 to liso-cel (100 × 106 chimeric antigen receptor-positive T cells) or SOC. Results are reported descriptively. With a median follow-up of 33.9 months, median (95% CI) event-free survival was 29.5 months (9.5 to not reached [NR]) for liso-cel versus 2.4 months (2.2 to 4.9) for SOC (hazard ratio [HR], 0.375; 95% CI, 0.259 to 0.542). Median progression-free survival was NR (12.6-NR) for liso-cel versus 6.2 months (4.3-8.6) for SOC (HR, 0.422; 95% CI, 0.279 to 0.639) with 36-month rates of 51% versus 26.5%. Median overall survival (OS) was NR for both arms (HR, 0.757; 95% CI, 0.481 to 1.191), with 66% of patients crossing over to receive liso-cel; 36-month OS rate was 63% for liso-cel versus 52% for SOC. OS HR (0.566 [95% CI, 0.359 to 0.895]) favored liso-cel when accounting for the treatment effect of crossover. Safety results were consistent with previous reports. At 3-year follow-up, liso-cel confirmed superior, more durable efficacy versus SOC with a favorable safety profile and no new safety signals. These data support liso-cel as an effective second-line treatment with curative potential for relapsed/refractory LBCL.

Introduction: Based on efficacy of CD22-targeted CAR T-cells in a phase I trial in adults with relapsed/refractory (r/r) large B-cell lymphoma (LBCL)—including in those with relapse following CD19 CAR T-cells (CAR19) (Frank M, et al. Lancet 2024), firicabtagene autoleucel (firi-cel/CRG-022), an autologous CD22-directed chimeric antigen receptor (CAR) T-cell therapy was tested in a Phase 2 study. Methods: The primary objective of this phase 2, open-label multicenter study was to evaluate efficacy of firi-cel in adults with r/r LBCL who progressed after CAR19 (cohort 1). The primary endpoint was overall response rate (ORR) as determined by blinded central review using Lugano Response Criteria. Cohort 2 was for those with a non-conforming product; cohort 3 was for those who received prior CAR19 and bispecific T-cell engagers. In contrast to the phase I study, CD22 expression was not required. Secondary objectives were to evaluate toxicity and additional efficacy endpoints, including ORR, complete response (CR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) as determined by individual investigators. Firi-cel was centrally manufactured using the Miltenyi Prodigy and utilized a different, more rapid in-culture timeline (5-9 days) compared to the phase I trial (7-12 days). Enrollment started Aug 2023 and data cut-off was 4/8/2025. Results: 138 patients underwent screening and 101 proceeded to leukapheresis (37 screen failures). 93 products were manufactured and 84 patients were infused. 15 patients dropped out due to manufacturing failures (7), disease progression (3), PI decision (4), or other (1). The median vein-to-vein time was 35 days (range, 24-86 days). For those infused, the median age was 65.5 years (19-87 years), 56 (67%) were male, 6 (7%) were non-white and 12 (14%) were Hispanic. The median number of prior lines of therapy was 3 (2-8) and the median time from prior CAR19 to apheresis was 7.4 months (1.6-66 months). 12 (14%) had bulky disease and 46 (55%) had elevated LDH. The median H-score for tumor CD22 expression was 65 (range 0-300). Among 52 patients with an available sample, 10 had undetectable CD22. At data cut-off (median follow-up of 4.8 months) and using investigator-determined responses (as central review was not available after trial closure), for cohort 1 (n=69), the ORR and CR rates were 73% (95% CI, 60-83%) and 46% (34-59%), respectively. The median DOR was 2.4 months (95% CI, 2.0-5.1). The median PFS and OS were 3.1 months (2.6-4.9) and 12.4 months (7.4-non-estimable (NE)). Results for cohort 2 (n=3) were comparable and will be reported later. For cohort 3 (n=12), the ORR and CR rates were 50.0% (21-79%) and 25% (6-57%) respectively. The median DOR was 2.2 months (1.1-NE), while the median PFS and OS were 2.8 months (0.9-3.4) and 5.9 months (2.8-NE), respectively. Any and grade 3+ CRS occurred in 66 (79%) and 4 (5%) patients. 8 (10%) had any grade ICANS with no Gr3+ seen. Immune effector cell associated hemophagocytic lymphohistiocytosis (IEC-HS) occurred in 21 (25%) subjects and was grade 3+ in 11 (13%). 5 (6%) had a fatal treatment-emergent adverse event, all related to IEC-HS or complications thereof. Firi-cel harvested after 5 (n=23), 7 (n=31), or 9 (n=15) days associated with 3-month CR rates of 32%, 15%, and 7%, respectively, and circulating firi-cel detectable in the peripheral blood in 91%, 58%, and 0% of patients at 3 months, respectively. Interestingly, day 5 products were enriched with central memory T-cells; while day 9 products were enriched with effector memory T-cells. CD22 tumor expression did not correlate with ORR or IEC-HS incidence or severity. Longer follow up is needed to determine whether CD22 tumor expression significantly correlates with DOR/PFS; so far patients with undetectable CD22 tumor expression trended toward shorter DOR/PFS. The trial was terminated due to limited durable responses and higher than anticipated toxicity.Conclusions: Firi-cel demonstrated high ORR in patients with r/r LBCL after prior CAR19. However, DOR was low likely due to altered manufacturing protocols and enrollment of patients with undetectable CD22 disease. Altered manufacturing may also have contributed to higher incidence and severity of IEC-HS. Further exploration of firi-cel pharmacokinetics and biology in relationship to toxicity will be essential to better understand the continued potential of CD22-targeting in LBCL.

Introduction:MCL remains incurable, and patients (pts) with relapsed/refractory (R/R) disease following Bruton tyrosine kinase inhibitor (BTKi) therapy face a poor prognosis and have a high unmet medical need. Anti-CD19 CAR T-cell therapy offers an effective therapeutic option in this setting. Currently approved CAR T-cell products demonstrate higher overall response rates than conventional therapies. However, their use is limited by restricted accessibility, prolonged vein-to-vein (VTV) times, considerable attrition rates, high rates of CRS and ICANS, and suboptimal durability of responses. Recently, a manageable safety profile of GLPG5101 with a median 7-day VTV time was reported in 61 pts with R/R non-Hodgkin lymphoma (NHL; 58/61 received a fresh product), demonstrating low rates of high-grade toxicities. Here, we present Phase 1/2 efficacy and safety data for pts with MCL in the ATALANTA-1 study. Methods: ATALANTA-1 (CTIS: 2022-502661-23-00; NCT06561425) is a Phase 1/2 study of GLPG5101 in pts with R/R NHL; Cohort 4 enrolled pts with R/R MCL. Primary objectives were safety and determination of the recommended Phase 2 dose in Phase 1, and efficacy in Phase 2. MRD was assessed using the clonoSEQ assay (Adaptive Biosciences, Seattle, WA, USA) in plasma and whole blood. Safety data are presented for the safety analysis set while efficacy and T-cell phenotypes of infused product are reported for the intention-to-treat (ITT) population across all doses received (50–110×10⁶ CAR T cells). GLPG5101 is a fresh, early memory-enriched phenotype CD19 CAR T-cell therapy, manufactured using a rapid decentralized platform enabling a 7-day VTV time. Results: As of 21 April 2025, 20 pts underwent leukapheresis. At the time of data cutoff, 18/19 (95%) pts had received an infusion and 1 pt was pending infusion. One pt discontinued the study prior to infusion due to progressive disease; a dropout rate of 1/19 (5%). A fresh product was received by 17/18 pts (94%) with a VTV time of 7 days; no pts required cytotoxic bridging chemotherapy. In the ITT analysis (n=20), median (range) pt age was 67 (57–81) years and median (range) number of prior systemic lines of therapy was 2 (1–6). All pts had received a BTKi, with 85% refractory to or relapsed while on BTKi. 14/20 (70%) pts had high-risk MCL International Prognostic Index scores; the remaining 6/20 (30%) had intermediate risk. 11/16 (69%) pts had a TP53 mutation, 8/12 (67%) pts had a Ki67 index ≥30%, and 3/20 (15%) pts had blastoid morphology. At the time of data cutoff, median (95% CI) follow-up duration was 8.7 (3.4, 16.1) and 6.9 (3.4, 15.1) months for infused pts and the ITT population, respectively. For the ITT population, excluding the pt yet to be infused, 18/19 pts responded with a complete response (CR), a 95% CR rate (CRR). All 18 infused pts achieved a CR (CRR 100%); 8/9 evaluable pts (89%) were MRD negative at the time of CR. The Kaplan–Meier (KM)-estimated 9-month duration of response rate was 82%; the KM-estimated 12-month progression-free survival (PFS) rate was 83%. During the treatment period (≤14 weeks post-infusion), the most common Grade (G) ≥3 adverse events were hematologic; serious infections were reported in 3/17 (18%) pts. G1/2 CRS was reported in 11/17 (65%) pts and G1 ICANS in 5/17 (29%) pts. There were no G≥3 CRS or ICANS events. G≥3 cytopenia was reported in 5/17 (29%), 4/17 (24%), and 4/15 (27%) pts at 30, 60, and 90 days post-infusion, respectively. One death occurred due to E. coli sepsis 6 months post-infusion, while the pt was in CR during the follow-up period (>14 weeks post-infusion). Compared with the starting material, the proportion of early memory phenotype CD8+CAR T cells increased significantly in the final product, and increased moderately within CD4+ CAR T cells, in 93% (13/14) of evaluable pts. These increases drove a corresponding reduction of terminally differentiated effectors. Conclusions: GLPG5101 achieved deep and durable responses in pts with high-risk, aggressive R/R MCL. GLPG5101, characterized by an early memory-enriched T-cell phenotype, was well tolerated, with no G≥3 CRS or ICANS, and demonstrated a 100% CRR, achieving 89% MRD negativity across both plasma and blood, and 83% 12-month PFS in infused pts. GLPG5101's short VTV time (7 days) and low dropout rate (5%) enabled a timely and well-tolerated treatment for pts with aggressive disease. These data support further development of GLPG5101 in a pivotal study for R/R MCL.

INTRODUCTION:Ulcerative jejunitis (UJ) or ulcerative enteritis (UE) is a rare complication of celiac disease (CeD). Guidelines regarding diagnosis and management are missing, and these cases have seldom been reported in the United States. DESIGN:Case series of CeD in which UE developed at a large academic center in the United States. Clinical presentation, diagnosis, treatment, and evolution of disease were collected. RESULTS:Eight cases were identified (6 male/2 female, mean age 59.5 [38-77] years). Presentations included intestinal obstruction (n = 3), GI hemorrhage (n = 3), and malabsorption (n = 2). Ulcers were present in the duodenum in 4 patients and exclusively past the angle of Treitz in only 4 cases, which makes the term UE more appropriate than UJ. Six of 8 had T-cell receptor clonal gene rearrangements, and 2 had definite aberrant T cells. Corticosteroids were tried in all patients without improvement, and 5 underwent surgical resection. Three patients received cladribine. One patient received an autologous stem cell transplant, followed by ruxolitinib. Two were subsequently diagnosed with enteropathy-associated T-cell lymphoma, including 1 with cerebral enteropathy-associated T-cell lymphoma, and 1 died from hemophagocytic syndrome. Two are still alive, including only 1 on GFD and 2 were lost to follow-up after surviving at least 30-month posttreatment. DISCUSSION:UE seems a more appropriate term to describe an ulcerative complication of CeD at high risk of obstruction or bleeding. Steroids were not effective. Treatment outcomes were variable, but with a 50% death rate.

Background With the advent of effective targeted therapy, there is growing interest in chemotherapy-free regimens in patients (pts) with mantle cell lymphoma (MCL). Triplet combinations of the BTK inhibitors ibrutinib or zanubrutinib, venetoclax (V), and obinutuzumab (O) have demonstrated efficacy in MCL, including TP53-aberrant disease (Le Gouill, Blood 2021; Kumar, Blood 2024). We hypothesized that acalabrutinib (A), in combination with VO (AVO) would be safe and effective in relapsed/refractory (R/R) and treatment naïve (TN) MCL. Methods In this investigator-sponsored, multicenter, phase I/II trial (NCT04855695), pts eligible for cohort A had R/R MCL after at least one anti-CD20 mAb-based therapy, cohort B had TN MCL ineligible for aggressive induction or TP53-aberrant MCL (TP53 mutation or >50% p53 expression on IHC). If safety and efficacy criteria were met in cohorts A or B, Cohort C would enroll TN TP53 wild-type pts eligible for aggressive induction. Pts were treated with A (100 mg po bid) starting cycle 1 (C1), O in C2 (100 mg IV D1, 900 mg IV D2, 1000 mg IV D8, D15) and D1 of C3-7, and V ramp-up in C3 to a target 400 mg daily. In all cohorts, O maintenance is given every 2 Cs between C9-C31. AV is continued indefinitely in cohort A, discontinued after achieving MRD negative (<1 in 106 cells by ClonoSEQ®) complete remission (CR) in peripheral blood (PB) for 3 months in cohort B, and optionally discontinued after MRD- CR in PB for 3 months in cohort C. Earliest discontinuation of AV was after 10 Cs in cohorts B and C. AV can be resumed at molecular or clinical relapse. Patients unevaluable for MRD received AV for 24 Cs. Primary endpoints were safety and tolerability for cohort A, CR rate after 7 Cs for cohort B, and MRD- CR rate after 7 Cs for cohort C. Results As of July 25, 2025, the study is fully enrolled (n=56). 20/20 pts in R/R cohort A, 24/24 pts in TN cohort B, and 11/12 pts in TN cohort C were evaluable for response. Median age was 65 (range 36-81). In cohort A, median number of prior therapies was 1, 20% relapsed after autologous stem cell transplant, 10% after CAR T cell therapy, and 30% had primary refractory disease. In cohort B, 79% pts (19/24) were TP53-aberrant, 71% (17/24) TP53 mutated, and 96% pts had advanced stage. MIPI score was 13% low, 21% intermediate, and 67% high risk. Ki67 ≥ 30% in 50%, Ki67 ≥ 50% in 29%, 54% complex karyotype, and 8% blastoid variant. In cohort C, 92% pts had stage IV, MIPI score was 33% low, 50% intermediate, and 17% high risk. Ki67 ≥ 30% in 33%, 25% complex karyotype, and 100% classic variant. In all pts, most common toxicities were headache (57%; all G1/2), bruising (41%; all G1), diarrhea (29%; 2% G3), and nausea (25%; all G1/2). ≥ G3 infections in 11% pts. Hematologic toxicity included neutropenia (46%; 30% G3/4), thrombocytopenia (32%; 9% G3/4), and anemia (29%; 5% G3). There was 2% febrile neutropenia, 2% atrial fibrillation, and 2 (4%) fatal toxicities due to COVID-19 and aspiration. No tumor lysis syndrome or ≥ G2 hemorrhage. Cohort A median follow-up was 24 months (range 7.3-39.4). Best ORR was 86% and CR rate 75%. 2-year progression-free survival (PFS) and overall survival (OS) were 75% (95% CI: 58, 97) and 86% (95% CI: 69, 100). Cohort B median follow-up was 20 months (range 0-26). Primary endpoint was met with CR rate 83% (ORR 88%). CR rate in TP53 mutated pts was 82%. 2-year PFS and OS were 78% (95% CI: 63, 97) and 96% (95% CI: 88, 100). Estimated 2-year PFS and OS for the 17 TP53 mutated TN pts were 82% (95% CI: 65, 100) and 94% (95% CI: 84, 100). 19/24 pts had evaluable MRD data. 15 pts (79%) achieved MRD- CR and 14 pts discontinued AV. 1 pt relapsed 4 months after discontinuing AV in MRD- CR and did not respond to AV retreatment. Median follow-up after AV discontinuation was 9 months. Cohort C median follow-up was 9 months (range 2-14.2). Best ORR and CR rate are both 100% (11/11). Estimated 12-month OS and PFS are both 100%. All 8 pts with evaluable MRD data achieved MRD- CR and 4 pts discontinued AV, with no relapses after a median follow-up of 3.5 months. Conclusions AVO is a well-tolerated and effective regimen in pts with R/R and TN MCL, with high rates of MRD- CR in TN MCL, allowing for MRD-guided time-limited therapy. The primary endpoint of TN cohort B was met, and the estimated 2 yr PFS and OS in the 17 TP53 mutated pts compare favorably with alternative regimens. Based on this data, the study will expand to include an additional 16 TP53 mutated pts.

Introduction Odronextamab, a CD20×CD3 bispecific antibody, showed compelling efficacy and generally manageable safety in patients (pts) with R/R B-NHL in ELM-2 (NCT03888105). Minimal residual disease (MRD), an exploratory endpoint of ELM-2, was initially assessed by ctDNA using the duplex CAPP-Seq method (AVENIO Oncology Assay NHL Test). Here, we evaluate MRD by ctDNA detected using phased variant tracking to determine whether this method more accurately predicts outcomes. Methods Raw AVENIO ctDNA sequencing data from plasma samples of pts with R/R follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL) in ELM-2 were re-analyzed to identify phased variants per Kurtz et al. (Nat Biotech 2021). Baseline (BL) tumor biopsies were not used to determine variants, reflecting realistic clinical sample availability. Phased variants were defined as 2 somatic mutations on the same DNA strand <170 bp apart. Triplet variants were not analysed. Identified BL phased variants had an allele frequency (AF) >1% (AF >0.2% for samples with no variants with AF >1%), but were filtered out if found in the germline sequence or in the healthy volunteer (HV) cell-free (cf)DNA blacklist (cfDNA was sequenced from 5 HVs). Remaining variants were “reporter phased variants”. The first on-treatment sample was taken at Week (Wk) 12 and used as a landmark to determine assay power in predicting clinical progression. Results In evaluable pts with R/R FL (n=65), the median number (range) of duplex reporter variants per pt (102 [0–323]) correlated moderately (rho=0.61) with the number of phased reporter variants (42 [1–9943]) at BL. In evaluable pts with R/R DLBCL (n=86), the observed correlation was similar (rho=0.59), although a lower median number (range) of reporter variants was detected by duplex (148 [0–529]) vs phased (680 [1–9765]) at BL. The relative amount of ctDNA (mutant molecules per mL [MMPM]) correlated significantly between the 2 methods in both FL and DLBCL (rho=0.65 and 0.83, respectively). In 3 BL samples, ctDNA was undetectable by duplex, but detectable by phased (with 8, 24, and 92 reporter variants). FL BL MMPM was highly predictive of progression-free survival (PFS) by both duplex and phased (HR: duplex 0.36 [95% CI 0.16–0.78] vs phased 0.33 [0.15–0.73]). This BL predicitivity was not observed in DLBCL. Concordance between the 2 methods at Wk 12 was 66.7% in FL and 66.3% in DLBCL. Undetectable ctDNA at Wk 12 was strongly associated with longer PFS in FL by both duplex and phased, with similar HRs (0.31 with both methods) and median PFS (42.4 vs 41.2 mos from Wk 12, respectively). In DLBCL, phased slightly outperformed duplex (HR in pts with undetectable ctDNA: 0.32 vs 0.42, respectively). When using Wk 12 ctDNA status to predict progressive disease (PD) (by Lugano criteria or given as reason for treatment discontinuation) the phased method showed a higher false negative rate in FL, with a sensitivity (true PD/all actual PD cases) of 0.52 (12/23) vs 0.83 (19/23) by duplex. Sensitivity was similar for both methods in DLBCL (duplex 0.80 [28/35] vs phased 0.77 [27/35]). Specificity (true non-PD/all actual non-PD cases) was slightly higher by phased (0.84 [31/37]) vs duplex (0.76 [28/37]) in FL, with this observation more pronounced in DLBCL (phased 0.7 [31/44] vs duplex 0.48 [20/42]) indicating a lower false positive rate with duplex. Beyond Wk 12, 2 pts with FL had undetectable ctDNA by duplex yet detectable ctDNA by phased at all timepoints, while remaining progression-free at 2 and 4 yrs. In contrast, 2 pts with detectable ctDNA by duplex but undetectable ctDNA by phased were progression-free after 2 yrs. In DLBCL, discordance was observed in 3 pts who remained progression-free (1 pt with undetectable ctDNA by duplex but not by phased, and 2 pts with undetectable ctDNA by phased but not by duplex). Conclusions ctDNA quantification by phased and duplex variant analysis correlated strongly, but ctDNA determination by phased did not consistently improve the power to predict PFS or PD. Phased method showed greater specificity in DLBCL, by better identifying pts with cleared ctDNA who did not progress, while the duplex method had greater sensitivity to identify FL pts who were ctDNA-positive and would later progress. Each approach has specific benefits, but both appear appropriate for MRD assessment, notably in pts with DLBCL. Further analyses of these methods across B-NHL subtypes are required to discern their relative advantages.

Introduction Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) both being approved for use. Axi-cel was approved for second-line setting based on studies showing improved outcomes compared to high-dose salvage chemoimmunotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). In contrast, tisa-cel did not demonstrate superiority over traditional salvage therapies in the second-line setting. Although both therapies are currently used in clinical practice, real-world comparative data on the safety of axi-cel versus tisa-cel remain limited. This retrospective study aims to compare the one-year outcomes of axi-cel and tisa-cel in patients with R/R DLBCL, offering practical insights into their outcomes outside of clinical trial settings. Methods A retrospective cohort study was conducted using TriNetX, a global federated health research network that provides access to electronic medical records from approximately 132 million patients, primarily in the United States. Adult patients (≥18 years) diagnosed with R/R DLBCL between January 1, 2022, and January 1, 2024, were identified using ICD-10-CM codes. Patients were categorized into two cohorts: those who received axi-cel and those who received tisa-cel. Propensity score matching (1:1) using nearest neighbor matching with a 0.1 pooled standard deviation caliper was performed for demographics, comorbidities, prior stem cell transplantation, and medications. Study outcomes included 1-year rates of all-cause mortality, all-cause hospitalization, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), anemia, neutropenia, thrombocytopenia, heart failure exacerbation, and acute myocardial infarction. Statistical analyses were conducted on the TriNetX platform, with significance set at P<0.05 (two-sided). TriNetX calculates hazard ratios (HRs) and cumulative incidences (CIs) using R survival package version 3.2-3 with the proportional hazard assumption tested using Schoenfeld residuals. This study does not require Institutional Review Board review or informed consent due to the use of de-identified data. Results Our study identified 1,250 patients with R/R DLBCL, including 1,083 patients who received axi-cel and 167 who received tisa-cel. After propensity score matching (PSM), 160 patients were in the axi-cel group (mean age 61.7 ± 11.8 years; 38.8% female; 73.1% White, 8.1% African American) and 160 patients were in the tisa-cel group (mean age 62.3 ± 16.0 years of age; 39.4% female; 75.0% White, 7.5% African American). Axi-cel group had 45% lower risk of all-cause mortality compared to tisa-cel group (HR: 0.55; 95% CI: 0.34–0.87). However, axi-cel group was associated with higher risks of all-cause hospitalization (HR: 1.33; 95% CI: 1.04–1.70), CRS (HR: 2.19; 95% CI: 1.43–3.36), and ICANS (HR: 2.69; 95% CI: 1.42–5.11) compared to tisa-cell group. No significant differences were observed in anemia (HR: 1.18; 95% CI: 0.82–1.72), neutropenia (HR: 1.30; 95% CI: 0.96–1.77), and thrombocytopenia (HR: 0.96; 95% CI: 0.65–1.43) between these two treatment groups. Additionally, there were no significant differences in terms of septic shock (HR: 0.79; 95% CI: 0.42–1.47), pneumonia (HR: 0.64; 95% CI: 0.34–1.21), and heart failure exacerbation (HR: 1.16; 95% CI: 0.76–1.76) between axi-cel group and tisa-cell group. Conclusion This large and multicenter cohort study provides real-world valuable insights into the one-year comparative outcomes of axi-cel and tisa-cel in patients with R/R DLBCL. Our study suggested axi-cel was associated with lower mortality rate, despites its higher rates of all-cause hospitalization, CRS, and ICANS compared to tisa-cell. These findings highlight the importance of close monitoring and supportive care during the first year following CAR-T therapy to optimize patient outcomes. An important limitation of our study is the lack of data on the number of prior lines of therapy, which may have differed between treatment groups and could have influenced clinical outcomes. Future prospective studies with comprehensive clinical data and inclusion of lisocabtagene maraleucel (liso-cel) would be valuable to provide a more complete comparison across currently available CAR T-cell therapies.

ABSTRACT:We analyzed the characteristics and outcomes of 95 patients with chronic lymphocytic leukemia (CLL) after Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i) failure. To clearly distinguish sensitivity and resistance to the targeted treatment classes, we defined double refractory (DR) CLL when progressive disease occurred during active treatment with a BTKi and a BCL2i, given sequentially or in combination, and double exposed (DE) disease when treatment with either or both of these agents was discontinued due to reasons other than progression. Thirty patients (31.6%) had DR CLL, and 65 (63.2%) had DE CLL. The DR group more frequently had unmutated immunoglobulin gene heavy chain variable (97%), TP53 aberration (73%), and BTK mutations (59%) than the DE group (75%, 46%, and 27%, respectively). The median number of total lines of therapy was 6 for DR and 3 for DE. Nearly all DR patients (97%) required subsequent therapy after developing DR CLL. The most commonly used treatment was noncovalent BTKis (34%), followed by concurrent covalent BTKi and BCL2i (28%) and CD19 chimeric antigen receptor-modified T cells (24%). Treatment for DE CLL was less frequently observed (26%). The median overall survival (OS) was 2.2 years once DR developed, despite the frequent initial responses to noncovalent BTKis or cellular therapy in the cohort. Patients with DE CLL demonstrated favorable survival (median OS not reached) and durable response to subsequent therapy.

ABSTRACT:Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post-CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell-associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

PURPOSE The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard-of-care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wild-type TP53 ; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk TP53 aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with TP53 aberration. METHODS This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration (ClinicalTrials.gov identifier: NCT03580928 ). Patients received acalabrutinib, obinutuzumab, and then venetoclax, with each treatment introduced sequentially and in combination, with the duration guided by measurable residual disease (MRD). Patients who achieved undetectable MRD (uMRD) after either 15 or 24 cycles could discontinue treatment. The primary end point was complete remission (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16. RESULTS Seventy-two patients were accrued, including 45 patients with TP53 aberration. The CR with BM-uMRD rates at the start of cycle 16 were 42% in patients with TP53 aberration and 42% in all-comers, and the BM-uMRD rates were 71% and 78%, respectively. Hematologic toxicities were mainly low grade, and cardiovascular toxicities and bleeding complications were infrequent. After a median follow-up of 55.2 months, 10 patients had progressed, including four with transformation, and three patients died. Four-year progression-free survival and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively. CONCLUSION AVO was highly active and well tolerated in patients with previously untreated high-risk CLL, supporting its use as a new standard-of-care treatment option.

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving immunotherapy for hematological malignancies. With increasing access to this modality, there is an urgent need for a comprehensive understanding of infectious complications to optimize routine monitoring, prophylaxis and improve clinical outcomes. Cytomegalovirus (CMV) remains a clinically significant pathogen in allogeneic and autologous hematopoietic cell transplant recipients, though the clinical implications of CMV reactivation after CAR T-cell therapy are poorly characterized. . We sought to perform a systematic review and meta-analysis of the published literature to determine the overall incidence of CMV following CAR T-cell therapy. Methods: The study was registered on PROSPERO and we searched 5 electronic (MEDLINE, EMBASE, CINAHL, Pubmed, Cochrane) from inception to 2022. Each author independently screened titles, reviewed full texts to identify eligible studies and extracted data from included studies using Covidence, a data extraction tool for conduction of standard systematic reviews. A random effects model was used, and proportions were used as a measure of outcome. We assessed heterogeneity using I^2 statistic. Risk of bias assessments were conducted using the RoB 2.0 for RCTs and ROBINS I tool for non-RCTs. Results Our search identified 12,441 studies of which 363 underwent full-text review. 30 studies were eligible for inclusion in the analysis and enrolled a total of 2536 patients. Among these, 18 were observational cohort studies, 10 were nonrandomized clinical trials, and 2 were randomized clinical trials. All studies enrolled patients with hematologic malignancies treated with CAR T-cell therapy. The majority of the studies included patients treated with CD19 targeted CAR T-cell therapy (n=23), compared to BCMA targeted CAR T cell therapy (n=2), multiple targets (n=2) and another investigational CAR T cell product (n=3). The median duration of follow up was ³30 days in 25 studies and <30 days in 5 of the included studies. The pooled incidence of an infectious event in adult patients after CAR T-cell therapy was 38% (95%CI 0.31, 0.46; p<0.01; I2 = 98%]. The pooled incidence of any infectious event was significantly higher in studies where patients were treated with a BCMA-directed CAR T cell agent (64%, 95% CI 0.53;0.74, I2 = 65%) compared to CD19-directed CAR T cell product (38%, 95% CI 0.29;0.47, I2 = 97%), p <0.01. Sixteen studies reported viral infectious events with an overall proportion of 36% (0.360, 95% CI 0.267 to 0.453) of the included subjects. Out of the 144 specified viral events, Cytomegalovirus was the most prevalent pathogen with a proportion of 21.53% (0.2153, 95% CI 0.1481-0.2824). Other commonly identified viral pathogens were rhinovirus, respiratory syncytial virus, and influenza with a proportion of 17.36% (0.1736, 95% CI 0.111- 0.2355), 9.72% (0.0972, 95% CI 0.0488-0.1456) and 8.3% (0.0833, 95% CI 0.0382-0.1285) respectively. Conclusions: Our findings suggest that viral infections are common and seen in about one third of patients after CAR T-cell therapy. Cytomegalovirus was the most commonly identified viral pathogen following CAR T-cell therapy and was responsible for approximately one-fifth of all viral infections reported. Further studies are needed to determine the impact and clinical outcomes of CMV infection following CAR-T cell therapy.