ABSTRACT:The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

PURPOSE Mutations in TP53 , detected in over 20% of diffuse large B-cell lymphomas (DLBCLs), are associated with poor prognosis. However, clinical outcomes among patients with TP53 -mutant disease vary, with some patients showing treatment responses similar to those with wild-type TP53 . This study aims to understand the clinical and molecular determinants underlying poor outcomes in TP53 -mutant DLBCL. METHODS Clinical and molecular data for 3,091 patients were derived from 10 cohorts of patients with newly diagnosed DLBCL treated with frontline rituximab-based immunochemotherapy regimens. Targeted or whole-exome/whole-genome sequencing was available for all patients. Bulk RNA-seq was analyzed for 591 patient samples. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS TP53- mutant DLBCL differed from wild-type disease in pattern and number of genetic lesions, malignant B-cell expression states, and tumor microenvironment composition. TP53 mutations were 6-fold more prevalent than MYC/BCL2/BCL6 double-/triple-hit status, but conferred similar adverse prognostic risk. Among patients with TP53 -mutant disease, variant allele frequency (VAF) further stratified risk, with patients featuring VAF ≥ 75% (indicative of loss of heterozygosity) experiencing significantly inferior PFS/OS. Downregulation of interferon signaling and lower macrophage content were identified in TP53 -mutant samples derived from patients with poor outcomes or VAF ≥ 75%. TP53 mutations were adversely prognostic among patients with DLBCL assigned to specific LymphGen subtypes (EZB, MCD), malignant B-cell states (S1), and ecotypes (LE4, LE7, LE8), whereas outcomes were similar to wild-type disease within other molecular subtypes. In re-examination of the Phoenix trial data, addition of ibrutinib to R-CHOP improved PFS in patients with TP53 -mutant DLBCL and abrogated the deleterious impact of high VAF, irrespective of patients' age. CONCLUSION The poor prognosis of TP53 -mutant DLBCL is dependent on intrinsic features, such as VAF, and modulated by co-occurring genomic lesions or lymphoma cell-intrinsic or microenvironmental expression patterns.

OBJECTIVE:We aimed to evaluate characteristics and outcomes of patients with locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) planned for chemoradiation, and the role of geriatric assessment (GA) in decision-making. METHODS:We included patients aged ≥60 years with LAHNSCC planned for chemoradiation referred to the geriatric oncology clinic between 2018 and 2023. RESULTS:Of 164 patients included, vulnerabilities were recorded in 36/148 (24.3%) patients assessed for functions and falls, 41/84 (48.8%) for comorbidities, 88/148 (55.4%) for nutrition, 26/148 (17.6%) for psychological, 6/87 (6.9%) for cognition, 25/84 (29.8%) for polypharmacy, and 8/148 (5.4%) for social domains. 76/148 (51.4%) were frail, with ≥2 vulnerabilities. 35 (21.3%) patients received radiotherapy alone; 117 (71.3%) patients received chemoradiation. Among 99 (86.4%) patients whose chemotherapy had not been planned prior to GA, chemotherapy regimen plan was changed after GA in 13 (13.1%). 24-month overall survival (OS) was 64.7% (95% confidence interval [CI]: 52.2%-80.3%). Factors significantly associated with poor OS were performance status (PS) ≥2 (hazard ratio [HR] 5.38, CI 2.39-12.1), vulnerability in nutrition (HR 2.52, CI 1.17-5.39), higher Cancer Aging and Research Group (CARG) chemotherapy toxicity score (HR 9.92, CI 3.91-25.16) and frailty (HR 10.51, CI 2.89-38.22). Factors associated with grade 3/4 toxicity included vulnerability in nutrition, higher CARG chemotherapy toxicity score and PS ≥2. CONCLUSION:Among older Indian patients with locally advanced head-and-neck squamous cell carcinoma planned for concurrent chemoradiation, 71.3% patients went on to receive concurrent chemotherapy following the GA. Frailty, vulnerability in nutrition, poor performance status and higher CARG chemotherapy toxicity prediction score were predictive for shorter survival.

Introduction In lymphoma, gut microbiome has been associated with clinical response to CD19 CAR T. In diffuse large B-cell lymphoma (DLBCL), the tumor microenvironment (TME) is a critical component contributing to the biology and potentially on patient outcomes. Intratumoral microorganisms (IMS) constitute a component of the TME in solid tumors and tend to localize in niches, interact with the TME and correlate with outcomes. Objective We analyzed IMS in DLBCL pre-CAR T hypothesizing that IMS might predict response. Methods Next-generation sequencing (NGS) targeting exons frequently somatically mutated in human cancers was performed on pre-CART samples from 83 patients (pts) with DLBCL at our institution. We mined the additional DNA that was incidentally deep sequenced from datasets for evidence of microbial presence in tumor samples. The control group comprised 71 lymph node samples from pts with suspected hematologic disorders where the same NGS revealed no mutations, and 266 untreated DLBCL samples. Microbial reads from regions that do not align with the human reference genome were analyzed. Several databases were referenced to exclude contamination, and IMS were deemed positive if a minimal number of 2 reads were present. For potential contaminants, the threshold of minimal number or reads was higher for each IMS, based on the literature. We compared variables with logistic and Cox regression analysis for survival for IMS present in more than 10% of the samples. Multiple test correction was performed with FDR. Results For 83 pts, median age at CART was 68 (32 – 81)y, 51 pts were male(61%), 44 pts had performance status(KPS) <90(53%), 36 pts had high pre-CAR LDH(43%), median lines pre-CAR were 3(min 2 max 7),stage at apheresis was III/IV in 62 patients(75%). Forty-three cases(52%), were germinal center (GC) derived and 30(36%) non-GC, not otherwise specified (NOS) in 10(12%) high grade (HG)BCL in 15(18%). Median number of IMS/sample was 9(min 1 – max 73) vs 3(min 0 max 90) in the controls, p=.02. Detection of specific IMSs was associated with achieving complete remission (CR) post CAR T: Neisseria (36/83, 43%, OR 0.33, p=.04, FDR q=.3), Rhodococcus (19/83, 23%, OR 0.14, p=.01, FDR q=.3), Lautropia (9/83, 11%, OR 0.1, p=.04, FDR q=.3 ), Prevotella (26/83, 31%, OR 0.34, p=.05, FDR q=.3). Detection of Campylobacter, Bordetella, Achromobacter, Lymphcryptovirus, Veillonella trended towards detection in CR patients. Detection of Neisseria (HR OS 2.00, 95% C.I. 1.1 – 3.6, p=.02, FDR q=.09), Moraxella (HR OS 3.89, 95% C.I. 1.41-11.1, p=.011, FDR q=.09), Rothia (HR OS=2.2, 95% C.I. 1.15 – 4.12, p=.01, FDR q=.09) were independent predictors of OS in Cox regression. Conclusions DLBCL were enriched of IMS compared to controls, and potential associations with treatment responses and outcomes were observed. Neisseria seems to be lymphoma-specific, associated with poor response to CART, and poor OS.

Addition of Bruton's tyrosine kinase inhibitor (BTKi) to first-line (1 L) bendamustine-rituximab (BR) improved progression-free survival (PFS) in patients with mantle cell lymphoma (MCL) in the SHINE and ECHO trials. We investigated whether sequential treatment with 1 L BR and second-line (2 L) BTKi can result in similar cumulative PFS compared to BR-BTKi combination therapy, using a multicenter cohort of 755 patients treated with 1 L BR between 2014 and 2020. Event-free survival (EFS), EFS2, and overall survival (OS) were analyzed. By intention-to-treat (ITT), EFS2 was defined as time from 1 L BR start to progression/relapse or retreatment following 2 L BTKi or death. After a median follow-up of 61.4 (95% CI 56.4-65.9) months, the median EFS after 1 L BR was 34.2 (95% CI 31.5-38.4) months. The median EFS2 following 1 L BR and 2 L BTKi by ITT analysis was 64.8 (95% CI 56.7-82.8) months, and the 5-year OS rate after 1 L BR was 57.9% (95% CI 54.1-62.0%), close to SHINE and ECHO results. Patients without high-risk features (high simplified MIPI, high Ki-67, blastoid/pleomorphic morphology, TP53 mutation, or complex karyotype) had more favorable survival outcomes. These results suggest that sequential treatment with 1 L BR and 2 L BTKi remains reasonable for select patients with MCL, particularly those without high-risk features.

Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.

High-grade B cell lymphoma (HGBCL) is an aggressive clinical entity characterized by poor overall survival and high rates of CNS relapse. HGCBL traditionally includes cases harboring MYC rearrangement with concurrent BCL2 and/or BCL6 rearrangements (R). However, the prognostic implications of different combinations of rearrangements (MYC/BCL2, MYC/BCL6, or MYC/BCL2/BCL6) remain an open question with differing reports in the literature, and our knowledge of the clinical characteristics, response to treatment, and patterns of relapse remains incomplete. We identified clinical data from 124 cases of advanced-stage HGBCL treated at Memorial Sloan Kettering Cancer Center (69 MYC/BCL2-R, 34 MYC/BCL2/BCL6-R ('triple hit') and 21 MYC/BCL6-R). Thirty-six cases were subjected to targeted next-generation sequencing with MSK-IMPACT HEME. We confirm the poor prognosis of HGBCL, with low complete response rates (44%), poor overall survival (59.8% at 2 years) and high rates of CNS relapse (10.1%). Intensive regimens such as dose-adjusted R-EPOCH were associated with improved overall survival compared to R-CHOP based regimens. Unexpectedly, patients with MYC/BCL6-R disease had increased incidence of CNS relapse and rapid progression to death after relapse; we observed differing cell-of-origin in these cases compared to BCL2-R disease. In addition, counter to prior reports in DLBCL, HGBCL transformed from low-grade lymphoma was associated with improved survival in our cohort. Mutational profiling of HGBCL cases demonstrated enrichment for mutations associated with DLBCL, particularly GC-derived cases, as well as a high proportion of MYC mutations. Our results support the poor prognosis of HGBCL and the recent separation of MYC/BCL6 disease as a distinct clinical entity.

INTRODUCTION:Sarcopenia is age-related loss of muscle mass and function. It is highly prevalent in older adults with cancer and is associated with adverse outcomes. Various consensus guidelines are available for assessing sarcopenia. Sarcopenia screening is not routinely done in geriatric oncology clinic. Data on the SARC-F questionnaire and its functional correlation with objective parameters are lacking from older Indian patients with cancer. MATERIALS AND METHODS:This was a retrospective observational study done in the geriatric oncology clinic at the Tata Memorial Hospital in Mumbai, India. We included patients aged ≥60 years who had undergone geriatric assessment (GA) and had completed the SARC-F questionnaire. Function was objectively assessed with hand grip and Timed-Up-and-Go test (TUG). We aimed to assess the utility of SARC-F by correlating it with the objective functional parameters and to find the association between grip strength and clinicodemographic parameters and vulnerabilities in various geriatric domains. RESULTS:Between November 2022 and October 2023, we enrolled 1025 patients. The mean age was 67 years (standard deviation, 5.8), 78.2% were male. Primary malignancies included gastrointestinal (36.7%), lung (27.7%), genitourinary (17.2%), and head and neck (16.2%). Palliative intent therapy was planned in 62.9% of patients. SARC-F was positive for sarcopenia in 24.2% (n = 248), while 58.8% (n = 603) participants had low handgrip strength, and 52.9% (n = 520) had prolonged TUG scores. SARC-F has a low sensitivity in identifying patients with low handgrip (sensitivity 29.6%, specificity 83.6%, negative predictive value [NPV] 45.4%, positive predictive value [PPV] 72.1%). SARC-F also has low sensitivity in identifying patients with prolonged TUG scores (sensitivity 35.9%, specificity 95.4%, NPV 57.03%, PPV 89.9%). Multivariate analysis using logistic regression showed that low handgrip strength significantly correlated with age, sex, TUG score, mid arm circumference, calf circumference, albumin level, clinical frailty scale, and the Cancer and Aging Research Group chemotherapy toxicity risk score. DISCUSSION:Simple objective measures of grip strength and TUG should be incorporated apart from SARC-F for screening of sarcopenia and assessing muscle strength in geriatric oncology clinic.

Triplet regimens induce high rates of undetectable MRD at ≤10-4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) CLL, but the optimal treatment duration to minimize the risk of neutropenia/infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL (NCT03824483). Our MRD-driven treatment/retreatment study was designed to optimize treatment duration balancing efficacy against toxicities associated with extended treatment exposure, and evaluate zanubrutinib-venetoclax (Z+V) retreatment. With a median observation time of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary endpoint). BOVen was well-tolerated with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; none grade 5). Median MRD4-free survival was 34.1 months (95% CI 23.1-50.5) and 48-month PFS was 79.7% (95% CI 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD by immunosequencing at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, p<0.001), and longer MRD4-free survival (50.5 vs 18.1 months, p<0.001) despite a shorter treatment duration (8 vs 13 mo, p<0.001). This manuscript also reports on the safety/efficacy of Z+V retreatment and describes pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent, early uMRD4 and durable remissions in TN CLL with a short treatment duration (median 10 months). ΔMRD400 is undergoing evaluation for use as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL.

Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous B-cell malignancy with variable prognosis, ranging from indolent, asymptomatic forms to aggressive subtypes with early treatment failure. Contemporary management emphasizes risk-adapted strategies that integrate patient characteristics, clinical disease burden, and tumor biology. Prognostic tools such as the MCL International Prognostic Index (MIPI) and its biologically integrated variant (combined MIPI), alongside assessment of Ki-67 proliferation, TP53 status, and blastoid morphology, help guide treatment selection. In younger, fit patients, first-line therapy traditionally involves dose-intensified chemoimmunotherapy with high-dose cytarabine and autologous stem-cell transplantation (ASCT). The incorporation of Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, into induction regimens has improved survival outcomes, with emerging evidence that may limit the use of ASCT to high-risk subsets. Maintenance therapy, particularly rituximab, remains crucial for durable disease control. In older or transplant-ineligible patients, bendamustine-rituximab remains a backbone therapy, with chemotherapy-free combinations incorporating BTKi, BCL2 inhibitors, and anti-CD20 antibodies offering effective, well-tolerated alternatives. High-risk patients, including those with TP53 mutations, may benefit from targeted triplet regimens or early cellular therapies. Relapsed/refractory MCL is increasingly managed with covalent and noncovalent BTKi, BCL2 inhibitors, and T-cell-redirecting therapies including chimeric antigen receptor T-cell therapy and bispecific antibodies. Ongoing trials are evaluating optimal sequencing and combination strategies to improve outcomes, particularly in high-risk and cBTKi-exposed patients. Overall, modern MCL management emphasizes individualized therapy based on biological risk, functional status, and treatment tolerability, with novel targeted and cellular approaches reshaping the frontline and relapsed treatment landscape.

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.

Introduction Treatment (tx) of older adults (OA) with mantle cell lymphoma (MCL) is evolving rapidly. Historically, chemoimmunotherapy (CIT) with bendamustine and rituximab (BR) +/- R maintenance was the preferred frontline (1L) treatment option in 'transplant ineligible’ patients, however, this paradigm has been challenged with the introduction of BTK inhibitors (BTKi). In OA, the ECHO study showed improved progression-free survival (PFS) of acalabrutinib-BR over BR, with acalabrutinib being continued indefinitely till progression. More recently, the ENRICH study showed an improved PFS for ibrutinib-rituximab (IR) over R-CHOP, with similar PFS as BR in OA. Concurrently, in eligible patients, high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) as 1L consolidation has been successfully challenged by incorporating BTKi in this setting. While chemo-free options with covalent BTKi+R represent an emerging, attractive tx option for OA, their limitations include indefinite tx and unique toxicities that can be challenging to manage in OA with multiple comorbidities. We interrogated the Memorial Sloan Kettering (MSK) Lymphoma Outcomes Database (LOD) to benchmark outcomes with CIT and to determine what insights can be gleaned from a predominantly CIT era to inform the future. Methods OA≥ 65 years (y) diagnosed (dx) with MCL treated at MSK from 2000-2025 were included. Pt demographics, disease/tx history and outcomes were extracted. PFS and OS were estimated using the Kaplan-Meier method, comparisons were made using log-rank test and associations between outcomes, clinical, and tx characteristics were evaluated with Fischer exact test. Results In 419 OA with MCL, median age was 72y (range 65-102y), age ≥80y 19%, male 73%, Stage 4 82%, MIPI low/intermediate/high 6%/47%/47%, blastoid/pleiomorphic 14%, Ki67 <30%/30-49%/≥50% 49%/25%/26%, p53 expression/17p deletion/TP53 mutation 10%/9%/10%. The proportion of women increased with age (p=0.06); no other age-based differences were noted at baseline. Median follow-up (f/u) was 8y (range 0.04-19.92y). Of the 28% pts managed with intent to observe at initial dx, median time on observation was 1.25 y (0.1-9.02y). Pts ≥80 yrs were more likely to be observed (p=0.036) with no age-based differences in median time on observation. Overall, 89% pts received a variety of 1L tx; majority received CIT (BR 33%, intensive regimens with intent to transplant 27%, R-CHOP 11%); 9% received BTKi in 1L; 25% pts were treated on clinical trials. After 1L therapy, 15% underwent HDC-ASCR consolidation and 22% received rituximab maintenance. Pts≥80y received anti-CD20 Ab monotherapy more frequently (24%). Overall response rate (ORR) was 75% with complete response rate (CRR) of 35%. The 5-y PFS was 37% (95% CI 32%, 43%) with 5-y OS of 61%. 5-y OS from receipt of 1L therapy was 56%. 45% pts have not required 2L tx to date. Age, gender, 1L tx type, stem cell transplant, stage, Ki67%, p53 expression, TP53 status, MIPI category, LDH level were significantly associated with PFS and OS (both from time of dx and start of 1L tx) in univariate analysis. Age, gender, 1L tx type, and Ki67% remained highly associated with PFS and OS in a multivariable model (MVA). Notably, women had a significantly better PFS to 1L tx (<0.001) and OS (<0.001) compared to men. Pts receiving intensive regimens with intent to transplant had longest mPFS (4.5y), followed by BTKi-based tx (3.6y), BR (3.1y) and R-CHOP (2y). Follow-up for BTKi exposed pts is immature to analyze the impact of BTKi use in 1L. Conclusions With a 5-y PFS of 37% and a 5-y OS of 61%, the outcomes of OA treated predominantly in the CIT era were consistent with contemporary CIT literature but suboptimal compared to modern regimens incorporating BTKi. Intensive CIT with intent to transplant led to durable remissions in carefully selected OA beyond the chronological age of 65y. PFS and OS significantly declined with advancing age despite comparable baseline characteristics suggestive of age-based bias in selecting 1L therapy and increasing toxicities to CIT. Our data highlights the need for continued investigation of chemo-free approaches in OA≥80y and the importance of incorporating fitness assessment for personalized decision making in OA. Women have a significant survival advantage over men and further analyses to understand gender-based differences in outcomes are planned.

Background: Molecular classifications of diffuse large B-cell lymphoma (DLBCL) can identify patient groups that benefit from distinct, innovative therapies. However, their implementation in routine practice has yet to be demonstrated. DLBclass (Chapuy, 2025) is a probabilistic, neural network–based classifier that assigns DLBCL cases to one of five genetic clusters (C1–C5). MSK-IMPACT Heme is a clinical NGS panel for detecting somatic mutations and allele-specific copy number alterations (CNAs) (Ptashkin, 2023). Here, we demonstrate how MSK-IMPACT Heme data collected during routine clinical care across various disease states enable the classification of cases into DLBclass clusters. Methods: DLBCL samples underwent MSK-IMPACT Heme sequencing along with clinical evaluation. This enabled the generation of DLBclass inputs: CNAs were called with FACETS, mutations annotated per Ptashkin (2023), structural variants identified by FISH, and cell-of-origin classified using the Hans algorithm. Technical validation: A total of 531 unique samples were initially assessed: 139 were excluded for low tumor purity (<20%) or failed FACETS quality control, resulting in a final cohort of 392 samples. This included 279 de novo DLBCL cases (184 pre- & 95 post-treatment) and 113 transformed indolent NHL (tiNHL) cases. Gene coverage of DLBclass cluster assignments ranged from 52% to 98% across the MSK-IMPACT Heme panels. Among the pre-treatment de novo DLBCL samples, cases were distributed across clusters as follows: 11% in C1, 28% in C2, 31% in C3, 12% in C4, and 17% in C5. Cluster C3 was significantly enriched compared to the published reference DLBclass datasets (p < 0.001), while the distribution of the other clusters mirrored that of the reference cohort. Using a 0.7 confidence threshold, we observed a lower proportion of high-confidence predictions in clusters C1, C4, and C5 relative to the DLBclass data. Across 45 matched samples with both WES and MSK-IMPACT Heme sequencing, cluster assignments were consistent in 71% of cases. Among the 13 mismatches, 12 involved cluster C2, highlighting variability in CNA-driven clusters between platforms. Given that C2 is primarily defined by CNAs, we investigated the impact of CNA removal on cluster assignment. Excluding CNAs led to a reduction in C2-classified samples, from 33% to 3.6%. Notably, in post-treatment samples, C2 had comprised 42%, underscoring its relevance in that clinical context. Upon CNA removal, many C2 samples shifted toward C3, suggesting that in the absence of CNAs, mutation profiles and panel breadth play a dominant role in cluster classification. Applying the DLBclass framework to routine MSK-IMPACT Heme data reproduced cluster patterns seen in reference datasets, validating its use in clinical samples and supporting further study of cluster biology and phenotypes. Biological and clinical correlations: In the de novo DLBCL cohort, the C3 cluster was significantly enriched for germinal center B-cell (GCB)–type cases, while C5 was more frequent among non-GCB cases (p < 0.001), both consistent with Chapuy (2025). Additionally, C3 and C5 showed enrichment for double/triple-hit lymphomas and primary CNS lymphomas (PCNSL), respectively. Cluster C2 was associated with low tumor mutational burden (TMB), whereas C4 correlated with high TMB. Patterns of progression-free survival mirrored those reported in the original DLBclass cohort, suggesting consistent clinical behavior across datasets. Among 15 patients with sequential samples, 80% retained stable cluster assignments over time. Changes in cluster confidence were mostly observed within C2, indicating overall low genomic heterogeneity across serial samples. Applying the DLBclass classifier to samples obtained after histologic transformation, we found that C3 was enriched in patients with prior follicular lymphoma, C2 in those with transformed chronic lymphocytic leukemia and marginal zone lymphoma (p < 0.001). MZL samples also showed enrichment in C5 (p < 0.003). Conclusion: Our findings are the first to demonstrate the feasibility and utility of applying the DLBclass genomic classifier to routine clinical samples using the MSK-IMPACT Heme assay. In our cohort, the classifier reproduced cluster distributions similar to reference datasets, establishing a basis for incorporating genomic subtyping into clinical workflows and improving molecular classification to guide personalized therapeutic strategies in DLBCL.

203 Background: Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are commonly diagnosed subtypes of B-cell non-Hodgkin lymphoma. To enhance awareness among community-based care teams, educational initiatives were developed to address the nuances of differential diagnosis and to spotlight emerging targeted therapies—particularly the use of Bruton’s tyrosine kinase inhibitors (BTKis) in the frontline setting. Methods: As part of a multi-phase educational initiative, Medlive surveyed community-based clinicians managing MCL and DLBCL. The MCL survey was conducted from March 2024 to June 2024, and the DLBCL survey from October 2024 to January 2025. We identified treaters of MCL and DLBCL in partnership with IQVIA; verified via ICD-10 codes. The surveys examined current practice patterns and management challenges in both disease areas. Results: A total of 77 clinicians responded for MCL and 81 for DLBCL, with the majority practicing in the community setting (71% for MCL and 83% for DLBCL). Clinicians in both groups reported incorporating biologic and molecular markers to guide treatment decisions. For MCL, the most commonly assessed markers were TP53 mutations/del 17p (61%) and Ki67 (55%), while in DLBCL, fluorescence in-situ hybridization testing for BCL2/BCL6 and MYC rearrangements was frequently performed (70% and 61%, respectively). Prognostic scoring tools were also utilized, with the MCL International Prognostic Index (MIPI) used in 58% of MCL cases and the revised International Prognostic Index (IPI) applied in 38% of DLBCL cases. Clinicians reported similar challenges in treatment decision-making for MCL and DLBCL, particularly selecting therapies based on current evidence (59% in both groups) and individualizing treatment plans (45% in MCL; 48% in DLBCL). Limited access to clinical decision tools (30% in MCL) and clinical trials (36% in DLBCL) were additional reported barriers. Physician perceptions of patient concerns mirrored these challenges, with both academic and community clinicians reporting that patients frequently struggled to understand their disease and available treatments (51% MCL; 44% DLBCL), were worried about treatment risks (51% MCL; 57% DLBCL), and found it difficult to choose the most appropriate treatment plan (47% MCL; 48% DLBCL). Although 53% of MCL clinicians currently use BTKis in practice, only 38% felt confident incorporating them as first-line therapy, despite current approvals in this setting. Conclusions: Findings from this initiative indicate that many clinicians face challenges in integrating BTKis into the treatment of patients with newly diagnosed B-cell lymphomas, largely due to limited access and insufficient familiarity with evidence-based strategies. These results highlight the ongoing need for targeted educational initiatives aimed at addressing these critical practice gaps and supporting optimal patient care.

Most patients diagnosed with mantle cell lymphoma (MCL) experience extended remissions following frontline chemoimmunotherapy, yet with with extended follow-up, relapses seem nearly inevitable. This study aimed to define the genomic landscape of MCL at diagnosis and relapse and investigate the clonal evolutionary dynamics associated with progression of disease (POD). We conducted comprehensive genomic sequencing on 214 tumor specimens from 189 patients, including 144 treatment-naïve and 70 POD samples, with 25 patients providing longitudinal paired samples pre-treatment and at POD. Comparative analyses were performed on single nucleotide variants (SNVs), insertions/deletions (indels), and copy number alterations (CNAs) to assess genomic differences between treatment-naïve and relapsed specimens. Additionally, mutational signatures were evaluated in pre-treatment samples, stratified by time to progression (≤24 months vs. >24 months). One hundred patients who received standard frontline chemoimmunotherapy were included in the survival analysis. Genomic profiles of pre-treatment specimens from patients who ultimately relapsed were strikingly similar to those observed in POD, while distinctly different from profiles associated with prolonged remissions. This genomic 'stability' was further confirmed by analysis of 25 paired specimens, demonstrating a remarkable genomic concordance despite extended remission periods (median >3 years), without a clear pattern of acquired alterations Our findings suggest that MCL relapse is predominantly driven by pre-existing malignant clones at diagnosis, rather than by new evolutionary events, underscoring the importance of early detection and eradication of resistant clones to improve long-term outcomes.

BACKGROUND: Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are two of the most diagnosed subtypes of B-cell non-Hodgkin lymphoma. Each presents unique diagnostic and therapeutic challenges, especially in community-based settings where access to novel agents and specialist expertise may be limited. In response to these needs, a series of four educational activities was developed as part of a six-phase initiative to support clinical decision-making, improve differential diagnosis, and raise awareness of emerging frontline targeted therapies for MCL and DLBCL. METHODS: Between 2023 and 2025, Medlive implemented four educational activities—two focused on MCL and two on DLBCL designed for expanded awareness for early recognition (broad audience) and for refined treatment strategies (specialty audience). To reach a broad audience, one MCL and one DLBCL activity was featured in the Medlive/National Organization for Rare Disorders (NORD) annual Rare Hematology Series. The other two activities were disseminated via nationwide networks to hematology/oncology specialists. For MCL, a 30-minute on-demand activity was made available from December 2023 to December 2024, followed by a 60-minute on-demand activity from June 2024 to June 2025. For DLBCL, a similar 30-minute activity ran from October 2024 to October 2025, with a 60-minute activity available January 2025 through January 2026. Learner outcomes were assessed through pre-/post-test questions to evaluate changes in knowledge and competence. Aggregate data on clinician-reported barriers to care and self-reported intent to change practice were analyzed. RESULTS: There were 2,731 participants across all four activities. In the MCL programs, 84% of participants were clinicians and 12% were nurses or advanced practice practitioners (APPs). For DLBCL, 81% were clinicians and 15% were nurses or APPs. Notably, 84% of all learners were hematologists/oncologists. Educational engagement revealed key barriers to optimal care. For MCL, the most cited obstacles included limited access to targeted therapies (21%) and unfamiliarity with novel treatment options (18%). For DLBCL, top barriers were unfamiliarity with novel therapies and access to targeted agents (33% each). Importantly, the education prompted approximately 40% of learners to report an intent to change their clinical practice. Across all four activities, the most common intended practice modifications include application of up-to-date treatment guidelines (50%) and revise therapeutic selection strategies (24%). When asked about systemic barriers to integrating new therapies, 44% of MCL and 48% of DLBCL treaters cited lack of knowledge of evidence-based approaches as the primary limitation. Secondary to those were disease-specific barriers: DLBCL clinicians frequently reported unfamiliarity with mechanisms of action (29%), while MCL clinicians pointed to limited experience with oral agents and continued reliance on traditional regimens (27% each). Furthermore, only 36% of hematologists/oncologists reported confidence in using BTK inhibitors for newly diagnosed MCL—despite the recent frontline approval of acalabrutinib-based combinations—highlighting a critical gap in knowledge and comfort with modern therapeutic options. Across all CME questions, knowledge improvements were observed, with an average increase of 15% in MCL programs and 26% in DLBCL programs based on paired pre-/post-assessment results. CONCLUSION: This multi-activity educational initiative successfully engaged clinicians who treat MCL and DLBCL, uncovering distinct challenges in clinical practice and highlighting persistent educational gaps. The findings affirm that while enthusiasm for integrating novel therapies exists, practical limitations such as lack of familiarity and barriers to access continue to hinder adoption. Given the evolving treatment landscape, particularly with the introduction of BTK inhibitors and other targeted agents in the frontline setting, continued clinician education is essential. These results emphasize the importance of ongoing, disease-specific, and multidisciplinary learning to improve confidence, address gaps, and ultimately enhance patient outcomes in MCL and DLBCL care. Support was provided by an independent educational grant from AstraZeneca Pharmaceuticals.

Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.