CD19-directed chimeric antigen receptor T-cell therapy (CD19-CAR) has yielded encouraging efficacy in CNS lymphomas (CNSL), but most patients ultimately experience progressive disease (PD). Risk factors, progression patterns as well as optimal salvage therapies remain unclear. Clinical and radiological characteristics of CD19-CAR failure were therefore retrospectively defined in CNSL treated at Massachusetts General Hospital from 2018 to 2024. PD patterns were defined as local or distant. CNS-progression-free survival from CD19-CAR infusion (CNS-PFS1) and first subsequent progression (CNS-PFS2) were analyzed. CD19-CAR achieved a 60

Introduction In the primary analysis of TRANSCEND FL (NCT04245839), an open-label, pivotal study, liso-cel showed high response rates and favorable safety in patients with R/R FL. Objectives To report 3-y follow-up (FU) results in patients with 3L+ FL, including efficacy, safety, and longitudinal safety analyses for key AEs. Methods Eligible patients had R/R FL after ≥ 2 prior lines of combination systemic therapy, including an anti-CD20 antibody and an alkylator. Patients received liso-cel after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response, PFS, OS, and safety. Additional post hoc analyses included time to next treatment and efficacy by progression of disease ≤ 24 mo from first-line chemoimmunotherapy (POD24) status (yes vs no) and by prior bendamustine exposure before leukapheresis (yes vs no). Incidences of infections, second primary malignancies (SPM), hypogammaglobulinemia, and grade ≥ 3 cytopenia (overall and by lineage) were assessed over time from Days 1–30, at 3-mo intervals until Month 12, at 6-mo intervals until Month 36, and from Month 36 until end of study. Results At data cutoff (03/31/2025), 107 patients with 3L+ FL received liso-cel and were evaluable for safety; 103 were efficacy evaluable. Median (range) age was 62 y (23–80); 95 (89%) had Ann Arbor stage III/IV disease; 61 (57%) were high risk per FL International Prognostic Index. Fifty-nine patients (55%) had POD24; 69 (64%) were double refractory to anti-CD20 antibody and an alkylator; 65 (61%) had prior bendamustine exposure.Median (range) on-study FU was 41.5 mo (0.3–54.0). Response rates were high overall and regardless of POD24 status or prior bendamustine exposure (Table 1).Treatment-emergent (TE) AE rates were consistent with the primary and 2-y FU analyses. Grade 3 cytokine release syndrome was reported in 1% (no grade 4/5) and grade 3 neurological events in 2% (no grade 4/5). SPMs were reported in 11 patients (10%; 4 additional patients since the 2-y FU analysis; no secondary T-cell malignancies). Grade ≥ 3 infections were reported in 13 (12%) patients, including 7 (7%) in the TE period (≤ 90 d after infusion) and 8 (7%) in the post-TE period (3 more patients since the 2-y analysis). AE incidences over time are shown in Table 2. Conclusion In patients with 3L+ FL, a single infusion of liso-cel demonstrated remarkable efficacy, with durable responses and high 3-y survival rates, regardless of POD24 status or prior bendamustine exposure. No new safety signals were identified. Grade ≥ 3 neutropenia and hypogammaglobulinemia decreased over time and severe infections remained low, further underscoring the favorable long-term safety profile of liso-cel in patients with 3L+ FL.

The non-covalent BTK inhibitor (non-cBTKi) pirtobrutinib (pirto) is approved for mantle cell lymphoma (MCL) patients with disease progression (PD) on cBTKi. We conducted a multi-center retrospective study on adult MCL patients with PD on cBTKi who received pirto outside of a clinical trial. 213 patients from 27 institutions were included (153 with non-bridging and 60 with bridging intent). In the non-bridging cohort, the overall response rate (ORR) and complete response rates were 34% (52/153) and 21% (32/153), respectively. At a median follow-up (mFU) of 16.4 months, median progression-free survival (PFS), overall survival (mOS), and duration of response were 5.3, 13, and 20.9 months, respectively. Inferior PFS was observed for ≤ 12 months on cBTKi (HR 1.77, 95% CI 1.21–2.59), Ki-67 ≥ 50% (HR 2.31, 1.50–3.56), and TP53 mutation (HR 1.78, 1.12–2.85). We then created a weighted risk score (0–5 points) to separate patients into low (0–1), intermediate (2–3), and high-risk (4–5). In the 60 patients treated with bridging intent, 45 (75%) were bridged (43 CAR-T, 2 allograft), and, at a mFU of 15.0 months, mOS was not reached. Compared to BRUIN, we report inferior outcomes for pirto in MCL patients with PD on cBTKi, while showing its benefit as a bridge therapy.

ABSTRACT:Tumor inflammation-associated neurotoxicity (TIAN) was recently proposed as a unique complication of immunotherapy in patients with brain tumor. Here, we report a first comprehensive characterization of TIAN in patients with central nervous system (CNS) lymphoma (CNSL) treated with CD19-directed chimeric antigen receptor (CD19-CAR) T cells. TIAN occurred in 10 of 56 (17.9%) patients with CNSL, with clinical onset at a median 3.5 days (range, 1-9) after CD19-CAR T-cell infusion. It was less frequently associated with cytokine release syndrome (60% vs 100%; P = .009) than immune effector cell-associated neurotoxicity syndrome (ICANS). Although symptoms were usually transient and fully reversible, TIAN was associated with a fatal outcome in 1 patient. Larger CNS tumor volume at baseline allowed the identification of patients at risk for TIAN (area under the curve, 0.847; P = .002). Maximizing Youden J statistics, a discriminatory tumor volume threshold of >3.4 cm3 was determined, which carried 87.5% sensitivity and 80.5% specificity. TIAN correlated with higher overall response rates to CD19-CAR T cells (90% vs 52%; P = .036) and improved progression-free survival (hazard ratio, 0.22; 95% confidence interval, 0.07-0.61; P = .006) on multivariate Cox proportional hazard regression. Postmortem histopathological evaluation of a TIAN lesion revealed a dense macrophage population with central necrosis and peripheral reactive gliosis, accompanied by loss of white matter and intracytoplasmic myelin in foamy macrophages. Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to preexisting CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management.

Primary testicular (PT) diffuse large B-cell lymphoma (DLBCL) is a rare and aggressive lymphoma with distinct clinical and molecular characteristics. To identify prognostic biomarkers in PT-DLBCL, in this study we analyzed DNA and RNA samples of PT-DLBCL tumors from 206 patients using next-generation sequencing platforms and assays. Genetic alteration analysis found that multiple chromosomal copy number variations (CNVs), TP53 transcript mutations with high variant allele frequency, and MCD subtype had significantly adverse prognostic effects, whereas elevated microsatellite instability had a significantly favorable prognostic effect in PT-DLBCL. Targeted RNA-seq analysis identified a PTL gene expression signature by comparing PT-DLBCL with systemic DLBCL and revealed the heterogeneity within PT-DLBCL by unsupervised clustering, which classified PT-DLBCLs into a testicular lymphoma tumor (TLT) subtype and a microenvironment (ME) subtype. The TLT subtype featured upregulation of genes functioning in DNA damage response, DNA repair, chromatin remodeling, the cell cycle, and the nucleus, and was associated with significantly poorer patient survival and higher frequencies of MYD88 mutations, multiple CNVs, MCD subtype, bulk tumors, and elderly patients in the PT-DLBCL cohort. In contrast, the ME subtype distinctively featured upregulation of various signaling pathway genes involving the tumor microenvironment and downregulation of BTK and B-cell receptor signaling genes, and was associated with significantly better clinical outcome than the TLT subtype of PT-DLBCL independently of CNVs, MCD and MYD88 mutation and than systemic DLBCL. Moreover, genomic microRNA profiling analysis identified a PTL microRNA signature significantly differentially expressed between PT-DLBCL and systemic DLBCL patients and within the PT-DLBCL cohort, and PT-DLBCL patients with higher expression of 16 PTL microRNAs (14 are testicular tissue-specific) had significantly better survival. In summary, this study revealed the molecular heterogeneity in genetic abnormalities and expression profiles of coding genes and microRNAs within the PT-DLBCL entity, and identified significant prognostic biomarkers and PTL signatures.

Abstract Background: In an evolving field with rapid changes in standard of care therapies, second opinions and multidisciplinary review (MDR) can inform the management of patients with cancer, yet these resources are not universally available. We gathered a panel of experts in hematology, medical oncology, surgical oncology, radiation oncology, and radiology, for MDR of over 400 anonymized complex cancer cases spanning various tumor types including hematological cancers. MDR treatment recommendations were captured. Herein, we analyze how the 3 most commonly used large language models (LLMs) performed, compared with the MDR expert panel recommendations, and compared with one another. Methods: We retrieved 38 complex malignant hematology cases previously adjudicated by MDR panels from the larger database of over 400 anonymized cancer cases collected and reviewed between 2020 and 2021. These cases were analyzed by 3 different foundational LLMs (OpenAI's ChatGPT 4.5, Anthropic's Claude Opus 4, and Google's Gemini Ultra) using PrecisCa's proprietary method for prompts. We then scored these recommendations from each system on a scale of 1-5 (5 being the highest) for 6 categories: completeness, reasoning, clarity, menu of options, recency, and relevance as compared to the MDR panel recommendations. The maximum possible competence score was 30 points per case, with a maximum aggregate score of 1,140 for all 38 cases. Final LLM recommendations were also reviewed in comparison with current National Comprehensive Cancer Network (NCCN) guidelines for serious omissions. Comparison in reverse (additional LLM options that the experts may have missed) was not performed, as many treatment recommendations have changed over the 4 years since the MDRs. Results: Patient characteristics included diagnoses of non-Hodgkin lymphoma (NHL) (n=15, 39.5%), multiple myeloma (MM) (n=14, 36.8%), Hodgkin lymphoma (n=5, 13.2%), and 4 individual cases of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia (n=4, 10.5%). The median age of all patients was 49.5 years (range: 21–78). Competence scores for ChatGPT 4.5, Claude Opus 4, and Gemini Ultra demonstrated an aggregate/median competence score (range) of 849/22.5 (15-30), 932/22.5 (15-30), and 964/22.5 (15-30), respectively. When assessing aggregate performance of all LLMs across diseases, they performed best in NHL cases, and the worst in MM ones. In NHL, menu of options was the highest rated category, while reasoning was theworst. In MM, completeness was best, and relevance was the worst. Overall, ChatGPT 4.5 performed worse than the other LLMs regardless of the disease category. Although there was some variation in the concordance and competence rates of the LLMs, all 3 had good concordance with the expert MDR recommendations. Discordant cases were reviewed and primarily involved minor differences that would not have altered the patients' management significantly. Conclusions: This study demonstrates good concordance between 3 leading LLMs and expert MDR recommendations for common yet complex hematologic cancer clinical scenarios. LLMs output may differ based on the disease in question. ChatGPT 4.5 overall was not as accurate as the other two evaluated LLMs in our admittedly small sample size. These findings suggest that LLM tools have continued to improve and may serve as valuable decision support aids in malignant hematology practice, particularly where expert review may be limited or unavailable. Careful human oversight remains essential to ensure safe and personalized cancer care.

R-CHOP as first-line (1L) therapy for LBCL has a cure rate of ~60%. However, ~10% of patients (pts) have refractory LBCL (Coiffier B et al, NEJM 2002) and ~30% of responders relapse within 2 years (Padala SA & Kallam A, In StatPearls. StatPearls Publishing; 2023). Autologous CAR T-cell therapies have been revolutionary in the treatment of relapsed/refractory (R/R) LBCL and they are considered standard second-line treatment but might not be an option due to aggressive disease, pt comorbidity, access barriers, or manufacturing issues/delays. Identifying responders to 1L therapy who are at high risk of relapse and rapidly administering an off-the-shelf CAR T-cell therapy for remission consolidation may improve outcomes. Presence of circulating tumor DNA (ctDNA)–based MRD, measured by an ultrasensitive MRD test at the end of 1L therapy, is highly prognostic for relapse. Cema-cel is an immediately available, off-the-shelf, HLA-unmatched allogeneic CD19 CAR T-cell product that utilizes Cellectis technologies has shown potent antitumor activity and manageable safety in phase 1 studies of pts with R/R LBCL and is a promising agent for consolidation in this treatment setting. The pivotal, randomized, open-label, phase 2 ALPHA3 study (NCT06500273) was designed to evaluate the efficacy and safety of consolidation with cema-cel compared with standard-of-care (SOC) observation in pts with LBCL who are in response after 1L immunochemotherapy but have detectable MRD by ctDNA-based testing. We report the updated study design.Study Design and Methods: Adults with histologically confirmed diffuse LBCL (DLBCL; includes DLBCL not otherwise specified, Epstein-Barr virus–positive DLBCL, DLBCL with IRF4/MUM1 rearrangement), high-grade B-cell lymphoma (HGBCL; includes HGBCL not otherwise specified, or with MYC and BCL2 and/or BCL6 rearrangements), or primary mediastinal B-cell lymphoma per WHO 2017 classification and ≥1 of the following clinical criteria at diagnosis—International Prognostic Index score of 2-5; Ann Arbor stage III/IV disease; and history of equivocal response at interim or end-of-therapy positron emission tomography (PET)/computed tomography (CT)—will be prescreened. Eligible pts must have completed a full course of standard 1L therapy that included an anthracycline and an anti-CD20 monoclonal antibody; achieved complete response (CR) or partial response (PR) suitable for observation at the end of 1L therapy per PET/CT evaluation by Lugano 2014 criteria and without evidence of progression by randomization; MRD positivity per ctDNA-based testing; Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. The study consists of a 2-part seamless design. In Part A, pts will be randomly assigned 1:1 to SOC observation or to cema-cel (120×106 CAR T cells) after a 3-day LD with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) (FC). Second cema-cel arm that utilized 3-day LD with FC plus the anti-CD52 monoclonal antibody ALLO-647 (30 mg/day) was closed in August 2025 because of a grade 5 hepatic failure event caused by a disseminated adenovirus infection that was attributed to ALLO-647. Part A will conclude with interim safety and surrogate biomarker–based efficacy analyses. In Part B, pts will continue to be randomly assigned 1:1 to cema-cel after FC or SOC observation. Randomization in Parts A and B will be stratified by best response to 1L therapy (CR vs PR). The primary endpoint is event-free survival per Lugano 2014 criteria by independent review committee (IRC), with hierarchical testing of key secondary end points of progression-free survival per Lugano 2014 criteria by IRC and overall survival. Other secondary end points include rate of MRD clearance and safety of cema-cel. Enrollment in Part A is ongoing. Pts randomly assigned to the treatment arm or followed up in observation during Part A will be included in the inferential testing in Part B. Approximately 110 pts will be enrolled in each arm across academic- and community-based centers. The study was initiated in June 2024.

The treatment landscape of B-cell lymphomas has significantly evolved in recent years with approval of novel targeted therapies. CD3 × CD20 bispecific antibodies and CD19-directed monoclonal antibodies and antibody-drug conjugates have demonstrated efficacy in relapsed/refractory follicular lymphoma (FL). Bruton tyrosine kinase (BTK) inhibitor-based regimens are emerging as effective treatment options for patients with TP53-mutated classical mantle cell lymphoma (MCL). Results from ongoing clinical trials suggest that the addition of CD3 × CD20 bispecific antibodies to chemoimmunotherapy improves outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, MCL, and DLBCL.

Abstract Background Glofitamab, a CD20xCD3 bispecific antibody, when combined with GemOx (Glofit-GemOx) has demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and complete response (CR) rate in patients with R/R DLBCL who are ineligible for autologous stem cell transplant (ASCT; Abramson et al. Lancet 2024). We report updated efficacy and safety of Glofit-GemOx versus R-GemOx, with 3 years of follow-up, in patients with R/R DLBCL after ≥1 prior line of therapy (LOT) from the global Phase III STARGLO trial (NCT04408638). Methods Patients were randomized 2:1 to either Glofit-GemOx (8 cycles plus 4 cycles glofitamab monotherapy) or R-GemOx (8 cycles) and stratified by number of prior LOT (1 vs ≥2) and refractoriness to last therapy. Following obinutuzumab pretreatment, glofitamab was given in Cycle 1 as weekly step-up doses (2.5/10mg), then 30mg target dose every 21 days from Cycle 2 Day 1. Patients enrolling after 1 prior LOT had to be ineligible for ASCT. The primary endpoint was OS. Secondary endpoints included independent review committee (IRC)-assessed PFS and CR rate. Landmark analyses of patients in CR at end of treatment (EOT) were conducted. Results Of the 274 (Glofit-GemOx, n=183; R-GemOx, n=91) patients with R/R DLBCL enrolled (intent-to-treat [ITT] population), 172 (62.8%) had 1 prior LOT, 102 (37.2%) had ≥2 prior LOT, 153 (55.8%) had primary refractory disease, and 166 (60.6%) were refractory to their last therapy. Of the patients with 1 prior LOT, 95 (55.2%) were primary refractory. Baseline characteristics were unchanged and balanced across arms. After 3 years of OS follow up (data cut-off: May 1, 2025; median follow-up: 35.1 months), Glofit-GemOx continued to demonstrate favorable outcomes versus R-GemOx in the ITT: median OS, 25.5 vs 12.5 months (hazard ratio [HR] 0.60, 95% confidence interval [CI]: 0.43–0.83); IRC-assessed median PFS, 14.4 vs 3.3 months (HR 0.41, 95% CI: 0.29–0.57); and CR rate, 58.5 vs 25.3%, respectively. The 36-month OS estimates were 47.1% for Glofit-GemOx and 27.4% for R-GemOx, and the 30-month PFS estimates were 38.1% for Glofit-GemOx and 15.2% for R-GemOx. Among patients who achieved CR at any time point (Glofit-GemOx, n=107; R-GemOx, n=23; median follow-up: 24.0 months), median duration of CR was not reached (95% CI: 27.2–not estimable [NE]) with Glofit-GemOx and was 24.2 months (95% CI: 6.9–NE) with R-GemOx. Amongst Glofit-GemOx-treated patients with a CR at EOT, the 24-month OS and PFS rates were 79.4% and 74.2%, respectively. A more pronounced efficacy benefit was observed for Glofit-GemOx versus R-GemOx in patients with 1 prior LOT: median OS, NE vs 14.4 months (HR 0.58, 95% CI: 0.38–0.89); median PFS, 20.4 vs 5.5 months (HR 0.49, 95% CI: 0.31–0.78); and CR rate (63.5 vs 28.1%). The 36-month OS estimates for these patients were 54.6% with Glofit-GemOx and 30.8% with R-GemOx, and the 30-month PFS estimates were 41.5% for Glofit-GemOx and 26.3 for R-GemOx. The safety profile was unchanged with extended follow up: no new signals were identified, and no evidence of cumulative toxicity or new long-term adverse events (AEs) were observed. In glofitamab-exposed patients, cytokine release syndrome (CRS) remained the most common AE (44.8%: Grade 1, 32.0%; Grade 2, 10.5%; Grade 3, 2.3%) and events consistent with immune effector cell-associated neurotoxicity syndrome occurred in 4 patients (all concurrent with CRS; most Grade 1–2 [n=3]). Infections and infestations occurred in 55.2% of glofitamab-exposed patients, with COVID-19 the most common infection (16.3%), occurring during the COVID-19 pandemic. Immune recovery was observed, with median B-cell and immunoglobulin M counts above the lower limit of normal 18–24 months after EOT. Glofit-GemOx treatment did not negatively affect T-cell levels. Conclusion After 3 years of follow-up, sustained benefits with Glofit-GemOx treatment were observed, demonstrating superior OS, PFS, and CR rates compared with R-GemOx in ASCT-ineligible patients with R/R DLBCL. Most patients that reached CR remained progression free and alive 2 years after EOT. A more pronounced efficacy benefit was observed for Glofit-GemOx versus R-GemOx in patients with 1 prior LOT. The safety profile remained consistent with the known risks of each study drug and was manageable. This updated analysis demonstrates the sustained remission and continued survival advantages that fixed-duration Glofit-GemOx offers for patients with R/R DLBCL.

Background: Frontline mantle cell lymphoma (MCL) treatments are rapidly evolving with incorporation of targeted therapies. We previously demonstrated the safety and efficacy of the BOVen triplet (Zanubrutinib, Obinutuzumab, and Venetoclax) in high-risk pts with TP53-mutant MCL (Kumar Blood 2025). In this phase II, multi-center, investigator-initiated clinical trial, we evaluated the safety and efficacy of BOVen for older MCL pts using a minimal residual disease (MRD)-driven, time-limited approach. Methods: Eligible pts had previously untreated MCL, requiring therapy, ≥65 years (yrs) of age or with comorbidities precluding autologous stem cell transplantation, and ECOG PS ≤2, ANC >1, PLT >75, HGB ≥9 (unless due to MCL). BOVen was administered in 28D cycles: Zanubrutinib (Zanu) 160 mg PO BID starting D1; Obinutuzumab (Obin) 1000 mg IV D1 or split D1-2, 8, 15 of C1, and D1 of C2-8; and Venetoclax (Ven) with standard ramp up dosing initiated C3D1 (target 400 mg QD). The minimum treatment duration was 24 cycles and if uMRD6 complete response (CR) was achieved after 24 cycles, then Zanu and Ven were stopped. The primary endpoint was 3-year progression-free survival (PFS). Responses were assessed per Lugano criteria. MRD was assessed serially using Adaptive clonoSEQ®in peripheral blood (PB) and bone marrow (BM). Results: 50 pts were enrolled across 3 sites; data cut April 30, 2025. The median age at enrollment was 72 years (range 47-89); 1 patient was <65 years of age, but transplant-ineligible due to cardiac comorbidity; 64% were male (32/50); various histologic subtypes were included (35 conventional MCL, 7 non-nodal leukemic, and 6 blastoid variant; 2 unclassified); by MIPI risk: 70% high (35/50), 22% intermediate (11/50), and 8% low (4/50); 51% Ki67≥30% (25/49); 29% Ki67≥50% (14/49); 28% TP53 mutation (13/46), and 20% 17p deletion (10/50). Median follow-up was 25 months (range 1.4-33.9). The best overall PET-based response rate was 98% (49/50) with 94% (47/50) achieving a CR. One patient with TP53, NOTCH2, CXCR4, BIRC3, and SMARCA4 baselinemutations progressed before cycle 3 and subsequently died of lymphoma. Three progressions and 5 deaths (2 disease-related, 1 viral encephalitis (possibly treatment-related), 1 hypoxemic respiratory failure due to aspiration pneumonia (treatment unrelated), and 1 sudden death likely due to an acute cardiac event (treatment unrelated)) were observed. One pt was lost to follow-up after C16. The 2-year PFS was 86% (95% CI: 77, 97). The 2-year OS was 92% (95% CI: 84, 100). MRD was evaluable in 98% (49/50) pts. MRD rates at a sensitivity level of 1x10-6 (uMRD6) were 28% at C3 (13/47; 1 without baseline ID sample, 1 early progressor, and 1 missed sample), 87% at C13 (39/45; 1 without baseline ID sample, 1 early progressor, 3 pts yet to reach C13), and 93% at EOT (28/30; 1 without baseline ID sample, 3 progressors, 3 deaths, 1 lost to follow-up, 12 pts yet to reach C24). 30 pts completed 24 cycles. Of these pts, 100% (30/30) achieved a CR and 24 stopped Zanu and Ven at EOT after achieving uMRD6 in PB. Of the 6 patients continued on oral therapy, 1 pt was MRD detectable (dMRD) in PB and BM at 1X10-6; and 5 patients were dMRD in BM, but uMRD6 in PB. The most common treatment-related AEs (TrAE, all grades, ≥10%) were predominantly low-grade and included diarrhea (n=23, 46%), neutropenia (n=17, 34%), thrombocytopenia (n=15, 30%), COVID-19 infection (n=14, 28%), fatigue (n=12, 24%), nausea (n=12, 24%), anemia (n=9, 18%), and infusion-related reaction (n=8, 16%), pneumonia (n=7, 14%), and upper respiratory infection (n=6, 12%). The most common grade 3 or higher TrAEs were neutropenia (n=10, 20%) including 2 grade 3 febrile neutropenia events and thrombocytopenia without bleeding (n=4, 8%). 11 patients experienced grade 3 or higher infectious events (1 viral encephalitis, 1 listeria bacteremia, 2 lung infections, 2 COVID-19 infections, 3 urinary tract infections, 1 prostatitis, and 1 upper respiratory infection). Summary/Conclusion: The MRD response-adapted BOVen triplet is highly active in older MCL patients with high rates of clinical and molecular response. The 2-year PFS rate of 86% is encouraging; however, extended follow-up is necessary to evaluate the 3-year PFS endpoint and the durability of response off treatment. Overall the regimen is safe and well-tolerated in older patients, with a toxicity profile similar to the prior experience with this triplet.

7040 Background: Recent data suggest circulating tumor DNA (ctDNA) can be detected in patients with classical Hodgkin lymphoma (cHL), with molecular response potentially complementing imaging assessments. We report on the use of an ultra-sensitive assay for ctDNA detection in patients with early-stage cHL to explore its utility in this population. Methods: In SGN35-027 (NCT03646123) Part C study, patients with stage I or II cHL without bulky disease (N=154) received brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) intravenously on days 1 and 15 of each 28-day cycle. Responses were assessed by PET/CT according to Lugano Classification with LYRIC at cycle (C) 2 day (D) 25-28 and end of treatment (EOT). 36 of 154 patients (23%) had plasma samples (collected at baseline, prior to C2D1 and C4D1, and EOT) analyzed for ctDNA using the PhasEDseq MRD assay. PET/CT results were compared with ctDNA dynamic changes in those with detectable baseline ctDNA. A genAI tool (12/19/24; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Results: Baseline ctDNA was detectable in 34 of 36 patients (94%) and was higher in patients with greater disease burden (indicated by baseline stage/risk status [ P =0.015] and International Prognostic Score [ P =0.014]). At C2D1, ctDNA was undetectable in 27 of 33 patients (82%). ctDNA levels decreased in all patients after 1 cycle of treatment. At C2 interim PET/CT, 18 of 34 patients (53%) achieved complete metabolic response (CMR); of these, 17 patients had ctDNA samples evaluable with 16 patients having undetectable ctDNA. The remaining 16 patients achieved partial metabolic response (PMR); of these, 5 patients had detectable ctDNA and 11 had undetectable ctDNA (all 11 patients with undetectable ctDNA achieved CMR at later time points). At C4D1, only 1 patient continued to have detectable ctDNA. At EOT, PET/CT showed that 26 of 34 patients (76%) achieved CMR, 5 achieved PMR, and 3 achieved indeterminate response (IR); none had detectable ctDNA at EOT. In long-term follow up (LTFU), 4 of the 5 PMRs eventually converted to CMR; 1 patient developed a second primary malignancy (mantle cell lymphoma). Follow up assessments during LTFU confirmed that 2 IRs converted to CMR and 1 converted to PMR. Conclusions: ctDNA was detectable in majority of patients with early-stage cHL at baseline, and higher levels are associated with increased disease burden. Treatment with AN+AD reduced ctDNA levels, with ctDNA becoming undetectable by EOT in all patients. In some patients, decline in ctDNA levels was observed earlier than responses observed through imaging, suggesting that ctDNA clearance may be an early indicator of treatment response. The potential value of ctDNA as a biomarker for early detection and monitoring of treatment response in early-stage cHL should be further investigated. Clinical trial information: NCT03646123 .

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p>0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=<0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

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.