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Abstract Background Mosaic chromosomal alterations (mCAs) are large-scale somatic gains, losses, or copy-neutral loss of heterozygosity (CNLOH) detectable by genotyping of peripheral blood DNA. They represent a form of clonal hematopoiesis and are observed in 0.5-5% of cancer-free individuals. The presence of any autosomal mCA has been associated with >3-fold risk of hematological malignancies. In particular, mCAs occurring in regions related to lymphoid malignancies have an 11-fold increased risk of lymphoid malignancies and a 68.6-fold risk for chronic lymphocytic leukemia (CLL). Monoclonal B-cell lymphocytosis (MBL), the precursor state to CLL, is defined by <5×10⁹/L clonal B cells in otherwise healthy individuals and is classified as low-count (<0.5x109/L) or high-count (0.5-5x10⁹/L) based on clonal B-cell count. MBL is also associated with increased risk of lymphoid malignancy (beyond CLL), with 4.3-fold and 74-fold risk in individuals with low- and high-count MBL, respectively. We previously reported a significant enrichment of autosomal mCAs in MBL, demonstrating a 1.7-fold association in those with low-count MBL and a 50.5-fold association in those with high-count MBL. Whether mCAs independently predict lymphoid malignancy risk after accounting for MBL status is unknown. Here, we evaluated the impact of mCAs on risk of incident lymphoid malignancies in individuals with MBL and in individuals screened negative for MBL. Methods CLL-type MBL (CD5 positive) was identified using flow cytometry assay on peripheral blood. Participants were age ≥40, had no prior hematologic malignancy, and were enrolled through the Mayo Clinic Biobank or the Division of Hematology at Mayo Clinic, Rochester. Participants were followed for incident lymphoid malignancy, including CLL, with diagnoses confirmed by medical record review. mCAs with cell fraction >1% were detected from array-based genotyping of whole blood DNA. Cox proportional hazards models, adjusted for age and sex, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of developing an incident lymphoid malignancy in individuals with autosomal mCA versus those without an autosomal mCA. Results In 4,331 participants with available MBL and mCA status, the median age was 67 years, and 45% were male. Flow cytometry identified 3,231 individuals who screened negative for MBL, 754 individuals with low-count MBL, and 346 individuals with high-count MBL. Autosomal mCAs were present in 6.5% of individuals without MBL, 7.6% with low-count MBL, and 71.1% with high-count MBL. Over a median follow-up of 6.9 years, 237 individuals developed an incident lymphoid malignancy. The most common types were CLL, multiple myeloma, and diffuse large B-cell lymphoma. Ignoring MBL status, the presence of an autosomal mCA was associated with increased risk of lymphoid malignancy (HR = 2.65; 95% CI: 1.45–4.86; P = 0.002), replicating previous results. However, after excluding individuals with MBL, this association attenuated; those with mCA alone did not have a significantly elevated risk (HR = 1.60; 95% CI: 0.57-4.52; P = 0.38) compared to individuals without MBL or mCA. We next examined the effect of mCAs among individuals with MBL. In those with low-count MBL, the most frequent mCA events were 13q loss (2.1%), 12 gain (1.9%), and 4q CNLOH (1.2%), and individuals with an mCA had a borderline significant risk of developing a lymphoid malignancy (HR = 2.78; 95% CI: 1.01–7.67; P = 0.049) compared to those without an mCA. Similarly, in those with high-count MBL, the most frequent mCA events were 13q loss/CNLOH (31.2%), 12 gain (13.0%), and 11q loss (4.9%), and the presence of an mCA conferred an increased risk compared to those without mCA (HR = 1.51; 95% CI: 1.09-2.08; P = 0.012). Conclusions Autosomal mCAs were more frequent in individuals with high-count MBL compared to those with low-count or no MBL. mCAs showed limited predictive value for lymphoid malignancy among individuals without MBL. In contrast, in individuals with low-count MBL, autosomal mCAs emerged as a potential biomarker for identifying those at risk of developing a lymphoid malignancy. In high-count MBL, mCAs were also a biomarker, but were driven by known chromosomal abnormalities identified through clinical testing. These findings suggest that the utility of mCAs as a predictive marker for lymphoid malignancy is contingent on the presence of MBL and may inform risk stratification and surveillance strategies in this population.

Abstract Background Secondary central nervous system lymphoma (SCNSL) is a rare but significant complication, affecting approximately 2–10% of patients with diffuse large B-cell lymphoma (DLBCL), often leading to poor outcomes. The CNS-International Prognostic Index (CNS-IPI) remains a widely adopted tool for estimating CNS relapse risk; however, recent advances in molecular profiling and evolving treatment paradigms have challenged the adequacy of CNS-IPI alone in guiding risk assessment. This study evaluates the prognostic relevance of CNS-IPI in conjunction with molecular and clinical factors, specifically cell-of-origin (COO), gene expression, and frontline treatment regimens. The aim is to refine risk stratification and identify patients at highest risk for SCNSL. Method Building on our previous study, we analyzed data from patients with newly diagnosed DLBCL between 2002 and 2023, enrolled in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource. Patients with primary CNS lymphoma, CNS involvement at diagnosis, or who received CNS-directed therapy were excluded. COO was determined using the Hans algorithm and/or Nanostring profiling. Multivariate cause-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for predictors of CNS relapse that were measured at the time of initial DLBCL diagnosis. Cumulative incidence with competing risks and cause-specific Cox models were used to analyze relapse risk. Result We included 2137 patients in our analysis, median age at diagnosis was 63 (IQR 53-72), with 41.6% (n=890) females. The albumin level was below normal in 32.5% (n=350), 64.0% (n=1367) had CNS-IPI of intermediate/high, 37.5% (n=586) had non-germinal center B-cell (GCB) COO, and 14.5% (n=309) were double expressor positive. At a median follow-up of 83 months (IQR 42 -143), 82 (3.8%) SCNSL relapses were observed; the 3 and 5 yrs cumulative incidence for SCNSL from time of DLBCL diagnosis were 3.7% (95% CI 3.0-4.7) and 3.8% (95% CI 3.1-4.8) respectively. In models accounting for death as a competing risk, the 5-year cumulative SCNSL incidence estimate for patients with a CNS-IPI low was 1.5% (95% CI 0.8-2.7), Intermediate was 4.9% (95% CI 3.7-6.4), and high was 6.1% (95% CI 3.8-9.6). The 5-year cumulative SCNSL incidence estimate for patients with non-GCB COO was 5.2% (95% CI 3.6-7.4) compared to 2.4% (95% CI 1.6-3.6; p=0.001) for GCB patients, and the 5-year cumulative SCNSL incidence for double expressor positive patients was 8.6% (95% 5.8-12.6) compared to 1.5% (95% CI 0.8-2.7; p<0.001) for double expressor negative patients. In a multivariable model (including CNS-IPI, COO, double expressor, treatment group, extranodal involvement, and albumin group), CNS-IPI intermediate (HR 2.85 [1.58-5.14]; p<0.001) and high (HR 4.31 [2.15-8.65]; p<0.001), non-GCB COO (HR 2.36 [1.37-4.06]; p=0.002], double expressor (HR 5.56 [2.88-10.73]; p<0.001), and below normal albumin (HR 1.89 [1.02-3.50]; p=0.042) were independently associated with increased risk of SCNSL. The majority of the SCNSL relapse occurred within the first 2 years after DLBCL diagnosis; 81.7% (n=67), with only 6.1% (n=5) occurring after 5 years. For patients who developed SCNSL, the median OS from the time of SCNSL diagnosis was 24 months (95% CI 17-34), with 5 years OS of 31% (95% CI 22-43). These findings are being validated using an external, international cohort, and final analysis will be presented at the time of presentation at ASH. Conclusion In this large, prospectively followed cohort with long-term follow-up data, SCNSL remains a rare but devastating complication of DLBCL, with a 5-year cumulative incidence of 3.8% and it is associated with very poor long-term survival. While CNS-IPI remains a strong predictor of SCNSL risk, our study identifies non-GCB COO and double expressor phenotype as independent, additive molecular risk factors. These findings suggest that current risk stratification tools may underestimate the risk of CNS relapse in molecularly defined high-risk subgroups. Considering the poor outcomes linked to SCNSL and the absence of a connection with frontline treatment types, future research should aim to enhance risk prediction models through molecular profiling and explore prophylactic strategies to reduce the likelihood of SCNSL.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma with limited prospective data to guide optimal therapy. This study evaluates real-world treatment patterns and survival outcomes using a large national cohort. Methods We analyzed data from the National Cancer Database (NCDB) for patients diagnosed with PCNSL between 2004 and 2020. Baseline demographics and treatment characteristics were analyzed using descriptive statistics. Survival outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were constructed to identify independent predictors of overall survival (OS). Results A total of 14,450 patients with PCNSL were included; 14,439 had first-line treatment data available, and 13,390 had survival data. Median age at diagnosis was 67 years (range 18-90), 49.2% were female, and 6.6% were African American. Chemotherapy alone was the modality of treatment for 81.6% (n=11,787), 12.2% (n=1,769) received chemoradiation, 3.8% (n=545) received chemotherapy and underwent autologous stem cell transplant (ASCT) but no radiation, and 2.4% (n=348) received radiation only. The median follow-up time was 73.5 months (95% CI 71.4-75.6), and the median OS for the group was 17.4 months (95% CI 16.2-18.6). Survival differed significantly by age group (median OS: <65 yrs, 46.1 months [95% CI 41.7 -50.6]; 65-79 yrs, 12.5 months [95% CI 11.2-13.7]; ≥80 yrs, 3.2 months [95% CI 2.9-3.5]; p<0.001), by year of diagnosis (median OS: 2004-2009, 11.0 months [95% CI 9.9-12.1]; 2010-2015, 20.0 months [95% CI 17.4-22.6], 2016-2020, 29.7 months [95% CI 26.0-33.4]; p<0.001), and by frontline treatment strategy (p<0.001). Patients treated with chemotherapy followed by ASCT had the longest median OS (not reached), while those receiving radiation alone had the poorest outcomes with a median OS of 3.9 months (95% CI 3.2-4.7); chemoradiation patients had a median OS of 31.8 months (95% CI 27.5-36.1), and chemotherapy only patients had a median OS of 13.9 months (95% CI 12.7-15.1)(p<0.001). African American patients had an inferior outcome with a median OS of 10.2 months [95% CI 7.2-13.1], compared to “other” races with a median OS of 36.9 months [95% CI 27.6-46.1] (p<0.001), although this is more similar to the median outcome for white patients (17.0 months [95% CI 15.8-18.3]). Treatment at an academic center (25.7 vs 11.0 months) and a high case-volume center (defined as >median number of cases per facility) (18.6 vs 10.5 months), and lower Charlson-Deyo comorbidity scores (CDS) (defined as CDS 0-1) (21.7 vs 6.8 months) were also associated with superior OS (p<0.001). In multivariable analysis, increasing age ( 65-79 y.o HR 1.60 [1.52-1.1.68], ≥80 y.o HR 2.95 [2.75-3.17]), CDS≥2 (HR 1.36 [1.28-1.44]), and African American race (HR 1.12 [1.02-1.24]) were adverse predictors of OS (all p<0.001), while treatment strategy (ASCT [HR 0.17], chemoradiation [HR 0.53], chemotherapy only [HR 0.68] compared to radiation alone), more recent year of diagnosis (2010-2015 [HR 0.81], 2016-2020 [0.70]), and treatment at an academic center [HR 0.81] remained predictors of superior OS (all p<0.001). Conclusion In this large national cohort of patients with PCNSL, treatment with chemotherapy followed by ASCT was associated with the most favorable survival outcomes. Patients treated with chemoradiation or multi-agent chemotherapy also demonstrated improved survival compared to those receiving radiation monotherapy or single-agent chemotherapy alone, respectively. Age, comorbidities, race, and treatment at academic centers were also significant independent predictors of OS. These findings highlight substantial disparities in outcomes and underscore the importance of optimizing treatment strategies, improving access to high-intensity therapies, and supporting timely referral to academic or high case-volume centers, particularly for younger and medically fit patients.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.

Abstract Introduction: Brentuximab vedotin (BV) was approved by the US FDA for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) in 2011 and for previously untreated advanced stage cHL in 2018. The immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab were approved for R/R cHL in 2016 and 2017, respectively. These novel agents have significantly changed the landscape of cHL management in recent years. In this study, we analyzed data from the National Cancer Database (NCDB) to investigate whether survival outcomes have improved in the novel agent era (2011 and beyond) for patients with cHL in the US. Methods: Patients diagnosed with cHL between 2004 and 2020 were identified in the NCDB. Those with missing survival data were excluded. Three treatment eras were defined based on the timing of FDA approval of novel agents: Chemo era (2004–2010), BV era (2011–2015), and ICI era (2016–2020). Patient and disease characteristics were compared using the Chi-square test. Survival analyses were conducted using the Kaplan-Meier method and Cox proportional hazards model. Results: A total of 85,488 patients with newly diagnosed cHL were identified: 36,150 in the Chemo era, 27,058 in the BV era, and 22,280 in the ICI era. Compared to the chemo era, the BV and/or ICI eras included slightly more patients aged ≥66 (17.3% vs 17.8% vs 19.5%), male (53.6% vs 54.6% vs 53.8%, p=0.042), Black (11.3% vs 12.9% vs 12.5%), Hispanic (9.0% vs 9.9% vs 10.9%), with Charlson-Deyo score ≥1 (14.2% vs 16.1% vs 17.2%), B symptoms (44.1% vs 46.9% vs 46.9%), treated at academic centers (32.4% vs 35.9% vs 36.4%), on Medicaid (9.5% vs 12.2% vs 13.7%) or Medicare (19.3% vs 20.3% vs 21.7%), and with higher income (≥4th quartile by 2008-2012 standard; 34.5% vs 34.3% vs 36.3%) (all p<0.001 except for sex, noted above). Ann Arbor stage data were not available in the ICI era. There were slightly more patients with advanced-stage disease in the BV era compared to the Chemo era (45.4% vs 40.3%, p<0.001). IPS scores were available for only 2,344 patients, with a similar distribution (0–2 vs 3–7) across the three eras (p=0.957). The median follow-up was 6.9 years (95% CI 6.9-7.0). Overall survival (OS) significantly improved in the novel agent eras: the 5-year OS rate was 79.8% (95% CI, 79.4%–81.2%) for patients diagnosed in the Chemo era, 81.9% (95% CI, 81.9%–82.4%) in the BV era, and 84.1% (95% CI, 83.5%–84.8%) in the ICI era (p<0.001). Statistically significant OS improvements were observed across all subgroups, including age (≤40: 92.8% vs 94.9% vs 96.5%, 41-65: 80.5% vs 81.8% vs 84.4%, ≥66: 41.4% vs 46.6% vs 52.7%), sex (male: 78.0% vs 80.0% vs 81.9%, female: 81.9% vs 84.1% vs 86.7%), race (White: 79.9% vs 81.6% vs 83.7%, Black: 77.2% vs 81.2% vs 84.6%, others: 84.5% vs 87.0% vs 89.3%), ethnicity (Hispanic 79.7% vs 82.3% vs 85.1%, Non-Hispanic 80.0% vs 81.9% vs 84.1%), Charlson-Deyo score (0: 83.5% vs 85.4% vs 87.9%, 1: 62.8% vs 68.2% vs 73.2%, 2: 42.5% vs 52.6% vs 58.3%, 3+: 49.0% vs 54.4% vs 51.7%), B symptoms (yes: 74.7% vs 78.9% vs 81.5%, no: 84.3% vs 85.1% vs 87.5%), treatment facility type (academic: 69.8% vs 74.0% vs 77.1%, non-academic: 66.4% vs 67.6% vs 70.2%, unknown: 92.9% vs 95.0% vs 96.5%), insurance type (private: 89.9% vs 91.2% vs 93.4%, Medicare: 46.5% vs 52.3% vs 57.2%, Medicaid: 79.1% vs 84.5% vs 87.7%) and income level (Q1: 74.1% vs 77.1% vs 81.1%, Q2 77.7% vs 80.1% vs 81.3%, Q3 79.8% vs 81.6% vs 85.2%, Q4: 82.8% vs 84.9% vs 87.0%) (all p<0.001). In multivariate Cox regression analysis adjusting for age, sex, race, ethnicity, Charlson-Deyo score, B symptoms, treatment facility type, insurance type, and income level, diagnosis in the BV era (HR = 0.856; 95% CI, 0.827–0.885; p<0.001) and ICI era (HR = 0.666; 95% CI, 0.636–0.698; p<0.001) was independently associated with improved OS compared to the Chemo era. Conclusions: In this large NCDB-based analysis, survival outcomes for patients with cHL significantly improved in the BV and ICI eras compared to the Chemo era. OS improvement was consistent across all subgroups and remained independent of age, sex, race, ethnicity, Charlson-Deyo score, B symptoms, treatment facility type, insurance type, and income level in multivariate analysis. These findings may reflect the positive impact of BV and ICIs on survival in patients with cHL.

PURPOSE Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed. METHODS The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L immunochemotherapy setting was performed using the prospective observational Lymphoma Epidemiology of Outcomes (LEO) cohort (N = 565) and three randomized phase III trials (N = 3,192); extension to all patients with FL (any 1L therapy) was performed in the LEO cohort (N = 1,445) and its Molecular Epidemiology Resource subcohort (N = 1,074). RESULTS The FLIPI24 model uses age and four blood-based variables (hemoglobin, lactate dehydrogenase, beta-2 microglobulin, and WBC count). FLIPI24 showed consistent performance across validation and extension data sets, which was superior to existing prognostic tools. Across the four external immunochemotherapy validation data sets, patients with high-risk FLIPI24 (23%-32% of patients) had significantly higher 24-month event rates (22%-35%) and inferior 5-year overall survival (77%-83%) compared with patients with low-risk FLIPI24 (29%-31% of patients, 24-month event rates: 10%-12%; 5-year OS: 96%-97%). Results were consistent when evaluating lymphoma-related death and when extended to all patients with FL. CONCLUSION The FLIPI24 model robustly stratifies, at diagnosis, patients with FL at increased risk of lymphoma-related death versus patients with very low lymphoma-related mortality during the first decade after diagnosis. FLIPI24 can be used to enrich future clinical trial designs in newly diagnosed FL.

PURPOSE The difference in time to serum calcium normalization and rates of subsequent refractory hypocalcemia between bisphosphonates requires further investigation. Our primary objective was to assess the difference in normalization of serum calcium between pamidronate and zoledronic acid during treatment of hypercalcemia of malignancy (HCM) and rates of subsequent, refractory hypocalcemia following therapy. METHODS A retrospective review of patients with cancer who received pamidronate or zoledronic acid inpatient at Mayo Clinic for treatment of HCM between January 2018 and January 2024 was conducted. Logistic regression evaluated the association between treatment groups and outcomes. Multivariable modeling was adjusted for baseline differences, including severity of hypercalcemia. RESULTS We evaluated 856 patients. The median age was 68 (IQR, 59-75) years, and 476 (55.6%) were male. The most common cancer diagnoses were lymphoma (n = 158, 18.5%), followed by multiple myeloma (n = 145, 16.9%) and lung cancer (n = 111, 13%). Overall, 292 (46.8%) patients and 154 (32.8%) patients achieved serum calcium normalization by hospital day 4 and day 7, respectively. The rate of normalization was similar between all bisphosphonates, regardless of pamidronate dose. Significantly higher rates of hypocalcemia were observed on day 4 for patients who received zoledronic acid 4 mg once compared with either dose (60 mg once and 90 mg once) of pamidronate (40.7% v 27.6% v 26.8%, P = .049, respectively). No significant difference in rates of hypocalcemia were observed on day 7 (56.8% v 50% v 42.9%, P = .26, respectively) and day 30 (39.1% v 39.0% v 37.5%, P = .50, respectively). CONCLUSION Bisphosphonates were equally efficacious in normalizing serum calcium in patients with HCM. Pamidronate 90 mg was not more efficacious than 60 mg. Rates of refractory hypocalcemia were similar.

Abstract This real-world retrospective cohort study evaluated utilization and comparative effectiveness of covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapies in relapsed/refractory mantle cell lymphoma (R/R MCL) from electronic health records in the United States. Adults with R/R MCL who received second- or third-line (2L/3L) zanubrutinib, acalabrutinib, or ibrutinib monotherapy, on or after 1 January 2018, were included. Inverse probability of treatment weighting was used in adjusted Cox models to compare real-world time-to-next treatment (rwTTNT) and overall survival (rwOS). Among 698 patients who received 2L/3L cBTKi monotherapy, 49%, 32%, and 19% received acalabrutinib, ibrutinib, and zanubrutinib, respectively. Unadjusted analyses showed median rwTTNT for 2L zanubrutinib, acalabrutinib, and ibrutinib was 14.5 (95% confidence interval [CI], 11.0-23.2), 12.8 (95% CI, 10.5-15.6), and 10.3 (95% CI, 7.6-13.7) months, and median rwOS was 26.4 (95% CI, 23.2 to not reached [NR]), 29.2 (95% CI, 22.9-38.1), and 29.3 (95% CI, 21.8-41.6) months, respectively. Median rwTTNT for 3L zanubrutinib, acalabrutinib, and ibrutinib was 21.1 (95% CI, 3.9 to NR), 9.2 (95% CI, 6.8-14.7), and 9.6 (95% CI, 4.8-18.0) months, and median rwOS was NR (95% CI, 27.3 to NR), 27.4 (95% CI, 15.1-42.2), and 27.0 (95% CI, 15.6 to NR) months, respectively. Adjusted models in the 2L/3L cohorts combined showed numerically longer rwTTNT and statistically significantly longer rwOS for zanubrutinib vs ibrutinib (hazard ratio, 0.63; 95% CI, 0.42-0.96), and trends for improved rwTTNT and rwOS for zanubrutinib over acalabrutinib. Toxicity was a frequent reason for changing to another cBTKi. These findings suggest potential improvements in rwTTNT and rwOS with the use of second- and next-generation cBTKis for R/R MCL from 2018 and beyond.

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used. Experimental Design: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77–3.84; P < 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66–4.02; P < 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5–0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.