Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7-32), which is comparable to what was observed in HR-SMM and does not meet the study's primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.

PURPOSE:Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS:The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS:After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION:The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Abstract Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, is approved for patients with relapsed/refractory multiple myeloma after 1 line of therapy. In the CAR-PRISM trial, we hypothesized that early use of cilta-cel in patients with high-risk smoldering myeloma (HR-SMM) would yield even higher efficacy with the potential for cure. Here, we report the initial safety and efficacy results from the complete study cohort. Methods: In this single-center, phase 2 study, patients received a single infusion of cilta-cel at target doses of 0.3, 0.5, or >0.5×106 CAR+ T cells/kg following lymphodepleting chemotherapy. No induction or bridging therapy was administered. High-risk SMM was defined by the 20/2/20 model or bone marrow plasma cells >10% with additional adverse features. Patients with >40% infiltration were excluded. Primary endpoint was the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (AEs); key secondary endpoints included overall response rate and minimal residual disease (MRD) negativity. Results: As of December 31, 2025, 20 patients (median age, 58 years; 6 women) received cilta-cel. No pre-specified DLTs were observed during the dose-escalation phase. The most common AEs were transient hematologic toxicities (neutropenia grade 4: 11/20, grade 3: 7/20; median duration 3 days). Cytokine release syndrome occurred in all patients (grade 1: 17/20, grade 2: 3/20). Non-ICANS neurologic toxicities (NINTs) occurred in seven patients, predominantly at the >0.5×106 dose level; five events were low grade and included facial palsy, tremor or paresthesia. Among two patients with movement and neurocognitive treatment-emergent AEs (MNTs); one patient’s work-up demonstrated CAR-T persistence and testing suggestive of a pre-existing synucleinopathy characterized by phosphorylated α-synuclein on skin biopsy and abnormal dopamine transporter imaging, whereas the other experienced grade 1 symptoms. Patients with NINTs showed significantly different longitudinal profiles, with higher absolute lymphocyte count (ALC, p<0.0001) and altered CD4:CD8 ratio (p=0.007), prompting dose reduction to 0.3×106 CAR+ T cells/kg and ALC-guided pre-emptive dexamethasone. At a median follow-up of 12 months, all patients achieved MRD negativity at 10-6 by 2 months, which is sustained. Of note, all six patients with follow-up beyond 18 months continue to have a sustained MRD negative status. For the 16 patients with ≥6 months of follow-up, the best overall response rate was 100% complete response. No progression or death events were observed. Conclusions: In this first study of CAR T-cell therapy in a precursor malignancy, cilta-cel induced rapid, deep, and sustained MRD-negative responses in all patients with HR-SMM in the absence of induction therapy. Biomarker-guided mitigation strategies may further optimize neurologic safety. Citation Format: Omar Nadeem, David Cordas dos Santos, Sarah Nikiforow, Kevin DeBraganca, Anna Bosch-Vilaseca, Elizabeth O'Donnell, Adam Sperling, Yuxin Liu, Frances Arters, Marjorie Marto, Amy Bergeron, Colin O'Donnell, Brendan Kineavy, Emilie Swenson, Kristin McHugh, Quentin Berry, Hope Wei, Emily Durlacher, Elizabeth Grimm, Rocio Montes de Oca, Denise De wiest, Robert Redd, Lorenzo Trippa, Caleb McIntire, Eric Smith, Kenneth Anderson, Nikhil Munshi, Deepu Madduri, Craig Tendler, Jordan Schecter, Mark Wildgust, Jerome Ritz, Irene Ghobrial. Ciltacabtagene autoleucel in high-risk smoldering myeloma: Results from the CAR-PRISM trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT103.

Abstract Multiple myeloma (MM) is an incurable plasma cell malignancy that is preceded by a presymptomatic state of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), conditions that together affect over 5% of adults over age 50. Although daratumumab was recently approved for the treatment of high-risk SMM, most individuals with MGUS or SMM undergo close observation alone, rendering an unmet need for the identification of alternative safe and cost-effective strategies to prevent disease progression. Metformin has demonstrated anti-myeloma activity in preclinical models and has been associated with reduced risk of progression to MM in observational studies; however, it’s efficacy has not been evaluated in a prospective trial. We conducted a phase II, single-center, randomized, placebo-controlled trial to assess the effect of metformin on serologic markers of disease progression in patients with high-risk MGUS and low-risk SMM (NCT04850846). Participants were randomized 1:1, stratified by heavy versus light chain disease and MGUS versus SMM, to 1500 mg daily metformin or placebo. The primary objective was to determine whether metformin reduced or stabilized serum monoclonal (M-) protein concentrations from baseline to 6 months, which is an established biomarker of disease burden. A total of 60 participants were randomized with a median age of 65 years. Half were male, 85% self-identified as White and 62% had SMM at study entry. Baseline characteristics and laboratory values were balanced across arms. The most commonly reported adverse events were nausea, diarrhea, and constipation. Forty-six participants had evaluable heavy-chain M-protein measurements at baseline and 6 months (median baseline M-protein, 0.94 g/dL). Among these participants, there was a median 3.2% decrease in serum M-protein among those randomized to the metformin group compared to a 7.7% increase in serum M-protein concentration among those randomized to placebo (p=0.015). Ten participants were only evaluable by serum-free light chains (sFLCs), and there was no difference across randomization arms in the changes in either sFLC ratios or difference between involved and uninvolved FLCs (both p>0.79). While clinical management for MGUS and many individuals with SMM has traditionally emphasized observation until progression to symptomatic MM, there remains strong interest among patients and clinicians in strategies to prevent or delay malignant transformation and subsequent end-organ damage. Short-term metformin use resulted in modest, but statistically significant changes in M-protein evolution in patients with heavy-chain MGUS and SMM. Although the magnitude of effect was smaller than those that can be achieved with cancer-directed therapies, these findings support further evaluation of metformin with longer follow up, as well as other metabolic interventions, as prevention strategies in precursor plasma cell disorders, especially among asymptomatic patients who are not candidates for and/or are unwilling to accept the risks of active treatment. Citation Format: Catherine R. Marinac, Robert Redd, Adam S. Sperling, Lorenzo Trippa, Victoria A. Kelly, Shonali Midha, Elizabeth K. O'Donnell, Paul G. Richardson, Irene M. Ghobrial, Omar Nadeem. Results of a randomized placebo-controlled phase 2 study of metformin for the prevention of progression of precursor multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT254.

Anthracyclines, which are key to many chemotherapeutic protocols, have been associated with increased vascular stiffness, a major factor associated with cardiovascular morbidity and mortality. There is no evidence-based intervention to prevent anthracycline-associated vascular dysfunction. To investigate whether atorvastatin pretreatment is associated with attenuation of the anthracycline-induced increase in aortic stiffness. This study is a secondary analysis of a double-blind, randomized clinical trial (Statins to Prevent the Cardiotoxicity From Anthracyclines [STOP-CA]). Enrollment occurred between January 25, 2017, and September 10, 2021, with the last follow-up on October 10, 2022. Primary analyses were reported on August 8, 2023. STOP-CA was a multicenter trial across 9 academic centers in the US and Canada. Participants were patients with newly diagnosed lymphoma scheduled to undergo anthracycline-based chemotherapy with no clinical indication for a statin. Atorvastatin (40 mg, once daily) or placebo for 12 months. This subanalysis of the STOP-CA trial includes post hoc end points with cardiac magnetic resonance imaging–derived aortic arch pulse wave velocity (PWV) and aortic distensibility (AD). An intention-to-treat approach was applied. The proportions of participants with a 1 SD or more increase in PWV and a 1 SD or more decrease in ascending aortic distensibility (AAD) were calculated in each group over 12 months. An increase in PWV of 0.15 m per second or more, a previously defined annual rate in individuals of similar age, was also assessed as a secondary end point. Of the 300 participants (150 randomized to atorvastatin and 150 randomized to placebo), 152 (mean [SD] age, 51 [17] years; 72 female [47%]; 82 treated with atorvastatin) had paired PWV data, and 168 had paired AD data. The PWV values remained similar in the atorvastatin group (mean [SD], 6.5 [1.9] vs 6.5 [2.0] m per second) but increased in the placebo group (5.7 [1.8] vs 6.8 [2.0] m per second) over 12 months. A 1 SD or more increase (0.8 m per second) in PWV was observed among 4 of 82 patients (5%) with atorvastatin and 35 of 70 patients (50%) with placebo (odds ratio, 0.05; 95% CI, 0.02 to 0.16; P < .001) at 12 months. A 1 SD or more decrease (1.8 × 10 −3 mm Hg −1 ) in AAD was observed among 6 of 88 patients (7%) with atorvastatin and in 14 of 80 patients (18%) with placebo. A 1 SD or more increase in PWV was associated with a mean left ventricular ejection fraction decline of 2.70% (95% CI, −4.65% to −0.81%; P = .006). Pretreatment with atorvastatin was associated with preservation of vascular function among patients with lymphoma undergoing anthracycline-based chemotherapy. ClinicalTrials.gov Identifier: NCT02943590

ABSTRACT:Venous thromboembolism (VTE) is a frequent occurrence in patients with cancer. However, it is not known whether treatment with different classes of anticoagulants impacts the risk of subsequent arterial thromboembolism. We performed a retrospective, population-based cohort study using Surveillance, Epidemiology, and End Results data linked with Medicare claims. Patients were eligible for study inclusion if they had a diagnosis of primary brain, colorectal, gastric, pancreatic, lung, or ovarian cancer between 2007 and 2015, were diagnosed with VTE, and had a prescription claim for a direct oral anticoagulant (DOAC), low-molecular-weight heparin (LMWH), or warfarin. We matched patients by propensity score in a 1:1:1 ratio into anticoagulant treatment groups based on their baseline demographic information, cancer-specific characteristics, and cardiovascular comorbidities. The primary aim of the study was to determine and compare the 6-month cumulative incidence of ischemic stroke across anticoagulant classes. The study comprised 4875 total patients with 1625 in each treatment group. At 6 months, the cumulative incidence of ischemic stroke was 5.6% (95% confidence interval [CI], 5.0-6.3) overall and 6.8% (95% CI, 5.6-8.1) in the DOAC, 4.9% (95% CI, 3.9-6.0) in the LMWH, and 5.2% (95% CI, 4.1-6.2) in the warfarin treatment groups (P = .040). We identified hypertension (odds ratio [OR], 1.75), atrial fibrillation/flutter (OR, 1.37), DOAC use (OR, 1.36), and previous stroke (OR, 3.59) as statistically significant risk factors for ischemic stroke in the multivariable modeling. In conclusion, ischemic stroke is a common occurrence after cancer-associated VTE and may occur more frequently in patients treated with DOACs.

Abstract: Use of brentuximab vedotin (BV) and PD-1 monoclonal antibodies (mAbs) before autologous stem cell transplantation (ASCT) could impact the benefit of post-ASCT BV maintenance in relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We identified 1091 patients with R/R cHL who underwent ASCT between 2010-2022. In total, 244 (22%) received a PD-1 mAb and 443 (41%) received BV before ASCT, while 305 (28%) received BV maintenance. We performed 1:1 propensity score matching to assess the efficacy of BV maintenance in different patient subgroups. Among 608 matched patients, the 3-year progression-free survival (PFS) and overall survival were 73% (95% confidence interval [CI], 70-78) and 95% (95%CI, 93-97), respectively. BV maintenance was associated with improved PFS for patients with no exposure to novel agents, especially those with 2+ modified AETHERA risk factors (0-1 factors: hazard ratio (HR), 0.51; 95%CI, 0.24-1.09; P =.083; 2+ factors: HR, 0.40; 95%CI, 0.25-0.65; P < .001). In contrast, BV maintenance was not associated with a significant PFS benefit for any patient subgroup who received novel agents before ASCT (BV-treated, 0-1: HR, 1.43; 95%CI, 0.53-3.81; P =.48; 2+: HR, 0.79; 95%CI, 0.34-1.82; P =.58; PD-1-treated, 0-1 [P >.99], 2+: HR, 0.25; 95%CI, 0.03-2.14; P =.21). In particular, we observed excellent outcomes for patients undergoing ASCT in a complete response after one line of PD-1-based salvage treatment with no significant benefit for BV maintenance observed (2-year PFS 100% vs 95%; P >.99). The benefit of BV maintenance appears to be attenuated for patients receiving novel agents with salvage therapy. Omission of BV maintenance should be considered for patients anticipated to have excellent outcomes.

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

High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to multiple myeloma, making it an ideal setting to test whether chimeric antigen receptor (CAR) T cell therapy can achieve curative outcomes. Here in this phase 2 study, patients with HR-SMM received ciltacabtagene autoleucel (cilta-cel) at 0.3-0.5 × 106 or >0.5 × 106 viable CAR+ T cells per kilogram without induction or bridging therapy. Patients with >40% marrow involvement were excluded. Primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events; secondary endpoints included response and minimal residual disease (MRD) negativity. As of 11 February 2026, 20 patients had been treated. The trial met the prespecified endpoints. No DLTs occurred. Adverse events included transient cytopenias (90% grade 3/4) and cytokine release syndrome (100% grade 1/2). Non-immune effector cell-associated neurotoxicity syndrome neurologic toxicities (NINTs) occurred in seven patients, with four comprising cranial nerve palsies that completely resolved. Three patients had persistent grade 1 symptoms. At a median follow-up of 15.3 months, all patients achieved MRD negativity 10-6 by 2 months and have remained MRD negative. Sixteen patients with follow-up >6 months achieved a complete response; no progression or deaths were observed. Cilta-cel produced rapid, deep, sustained MRD-negative responses in HR-SMM without induction therapy. Toxicities were consistent with the safety profile of cilta-cel. ClinicalTrials.gov: NCT05767359 .

Background Fludarabine and cyclophosphamide form the standard lymphodepletion regimen for chimeric antigen receptor (CAR) T-cell therapy, including ciltacabtagene autoleucel and idecabtagene vicleucel, in relapsed or refractory multiple myeloma (RRMM). While clinical trial protocols recommend renal dose adjustments for fludarabine, institutional practices vary. At Dana-Farber Cancer Institute (DFCI) and Brigham and Women's Hospital (BWH), patients with creatinine clearance (CrCl) 50–69 mL/min receive full-dose fludarabine, while those with CrCl 30–49 mL/min receive a 40% reduction. Objective To compare the safety and efficacy of varying fludarabine renal dosing practices for lymphodepletion in multiple myeloma patients undergoing CAR T-cell immunotherapy. Methods This single-site, retrospective medical record review included adults with RRMM who received fludarabine and cyclophosphamide lymphodepletion before ciltacabtagene autoleucel or idecabtagene vicleucel at DFCI/BWH from August 2021 to June 2024, with ≥30 days of follow-up post-infusion. Patients were grouped by renal function: CrCl ≥70, 50–69, or 30–49 mL/min. The primary outcome was adverse events (AEs) within 30 days of CAR-T cell infusion; secondary outcomes assessed efficacy. Continuous variables were summarized as median and inner quartile range (IQR) and categorical variables as proportions. Statistical associations used Wilcoxon rank-sum or Fisher's exact tests. Results Among 101 patients, cytokine release syndrome (CRS) occurred in 82%, 100%, and 82% of patients in the CrCl ≥70, 50–69, and 30–49 mL/min groups, respectively (p=0.15); most were grade 1–2. ICANS occurred in 10%, 12%, and 0% (p=0.62). Infection rates were 14%, 12%, and 18% (p=0.90). Rates of anemia, thrombocytopenia, and neutropenia were similar across groups (all p>0.40). Median percent ALC decrease was 94.7%, 97.7%, and 96.5% (p=0.45). Overall response rates were 88%, 94%, and 91% (p=0.87), with most achieving CR or sCR. Median progression-free survival was 12, 19 and not reached months (p=0.13); median overall survival was not reached across groups (p=0.33). Conclusion Maintaining full-dose fludarabine for patients with CrCl 50–69 mL/min did not increase toxicity, while those with CrCl 30–49 mL/min receiving reduced doses maintained efficacy. These findings support institutional dosing practices and demonstrate comparable safety and efficacy across renal function groups.

Background: Increased aortic stiffness is associated with cardiovascular morbidity and mortality, and is an adverse effect of anthracyclines. To date, there is no evidence-supported intervention that preserves vascular function among anthracycline recipients. While statins have been shown to preserve vascular function in patients not treated with anthracyclines, their effectiveness in patients treated with anthracyclines remains unclear. Hypothesis: We hypothesized that atorvastatin would protect against the anthracycline-induced deterioration of vascular function, assessed by aortic pulse wave velocity (PWV). Methods: We conducted a post-hoc analysis of cardiac MRI-derived PWV data from participants with newly diagnosed lymphoma in the STOP-CA trial, who were scheduled to undergo anthracycline-based chemotherapy and randomized to atorvastatin or placebo for 12 months. In patients with available data, PWV was measured at baseline and 12 months. The primary endpoint was a ≥1 standard deviation (SD) increase in PWV. The secondary endpoint was a ≥0.15 m/s increase, a previously identified mean annual rise in patients with increased cardiovascular risk. Incident heart failure (HF) events were evaluated at 24 months. Results: Paired PWV data were available in 152 participants (mean age 51±16 years, 47% female, 82 with atorvastatin). Age (median 56 for atorvastatin vs. 52 years for placebo, p=0.11) and baseline PWV were higher in the atorvastatin group (6.5±1.9 vs. 5.7±1.8 m/s, p=0.016). At 12 months, PWV was similar between the groups (6.5±2.0 vs. 6.8±2.0 m/s, p=0.47). The mean interval change in PWV was significantly lower in the atorvastatin group (0.1±0.5 vs. 1.0±0.9 m/s, p<0.001). A ≥1SD increase (0.8 m/s) was observed in 5% of the atorvastatin and 50% of the placebo groups (odds ratio [OR] 0.05, 95% confidence interval [CI] 0.02-0.16, p<0.001). A ≥0.15 m/s increase in PWV was noted in 37% of the atorvastatin and 89% of the placebo group (OR 0.08, 95% CI 0.03-0.19, p<0.001). A ≥1 SD increase in PWV was associated with a mean LVEF decline of 2.7% (95% CI -4.65 to -0.81, p=0.006). All participants (n=8) who developed incident HF by 24 months had a ≥0.15 m/s increase in PWV (p=0.023). Conclusion: In lymphoma patients undergoing anthracycline-based chemotherapy, atorvastatin demonstrated vasculoprotective effects by reducing the odds of a significant increase in aortic stiffness over 12 months. An increase in PWV may be associated with a higher risk for subsequent HF events.

Introduction Though transformed indolent lymphomas (tiNHL) have historically been associated with poor outcomes in the relapsed or refractory (R/R) setting, novel treatments e.g. chimeric antigen receptor (CAR) T-cells offer some improvement. Bispecific antibodies (BsAbs) are effective in R/R large B-cell lymphoma (LBCL), but their activity in tiNHL is not well characterized. The goal of our study is to explore the clinical efficacy and safety of BsAbs delivered outside of clinical trials in R/R tiNHL, compared to de novo diffuse LBCL not otherwise specified (NOS) (dnDLBCL) using an adapted propensity score matching (PSM) analysis. Methods We conducted a multicenter retrospective study across 9 centers that are part of the Collaborative US Bispecifics Consortium (CUBIC). The study included adults (≥18 years old) with R/R tiNHL or dnDLBCLtreated with CD20xCD3 BsAbs (epcoritamab or glofitamab), outside of clinical trials from May 2023 to May 2025. We defined tiNHL as LBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL), or low-grade B-cell lymphoma NOS. Patients (pts) with Richter's syndrome were excluded. To balance covariate distribution between the tiNHL and dnDLBCLcohort, an exhaustive list of covariates was used for PSM: age, sex, race, ethnicity, number of prior lines of treatment before BsAb, prior treatment line by CAR T-cells therapy, prior autologous stem cell transplantation (ASCT), performance status (PS), B symptoms, Ann Arbor stage, central nervous system involvement, >1 extranodal site of involvement, LDH, specific BsAb and year of BsAb initiation. PSM was performed considering a 1:1 matching. The primary outcomes were the overall response rate (ORR) and complete response rate (CRR), assessed by local investigators using the Lugano 2014 criteria. Secondary outcomes included progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The study was approved by the Institutional Review Board at each site. Results 61 pts with R/R tiNHL and 157 pts with dnDLBCL were included in the study. Among the tiNHLs, 80% arose from FL, 10% from MZL, 4% from WM/LPL and 5% from a low-grade B-cell lymphoma NOS. At treatment initiation, 69% of tiNHL had DLBCL NOS, 23% high-grade B-cell lymphoma, 3% T-cell/histiocyte-rich LBCL and 3% LBCL without further specification. Following the 1:1 matching process, the study included a total of 122 pts (61 tiNHL and 61 dnDLBCL). At the time of BsAb treatment, among the tiNHL and dnDLBCL cohorts, respectively, 43%/48% received epcoritamab while 57%/52% received glofitamab; the median age was 72 years (range: 38-91)/71 years (23-89), 41%/44% were female, the median number of prior lines received was 3 (range: 1-9)/ 3 (1-7), 52%/51% had previously received CAR T-cells, 8%/5% had a prior ASCT, 15%/33% had ECOG ≥2, 79%/79% had advanced-stage disease (III-IV), 46%/52% had >1 extranodal involvement and 61%/57% had LDH above the upper normal limit. With a median follow-up of 8.9 months, efficacy outcomes were comparable. The best ORR/CRR was 51% (95% CI, 38-64)/33% (95% CI, 21-46) for the tiNHL cohort and 49% (95% CI, 36-62)/33% (95% CI, 21-46) for the dnDLBCL. 56 pts died, 28 in each cohort. No significant differences were observed between the two cohorts (tiNHL vs dnDLBCL respectively) for the 6-month PFS (34%, [95% CI,23-50] vs 34%, [95% CI, 23-48], p=0.78), 6-month OS (56%, [95% CI,43-72] vs 56%, [95% CI, 44-71], p>0.99), and 6-month DOR (49%, [95% CI,32-76] vs 52%, [95% CI, 34-78], p=0.71). Among tiNHL pts, no differences were observed for response rate, OS and PFS, based on the type of BsAb. Similar toxicities were observed in both cohorts. In tiNHL and dnDLBCL cohort, respectively, any grade CRS were observed in 41% and 36% pts (p=0.84) and any grade ICANS in 11% and 15% pts (p=0.58). In tiNHL cohort 25 pts experienced CRS (grade 1: 16, grade 2: 7 and grade 3: 2) and 7 experienced ICANS (grade 1: 3, grade 2: 3 and grade 3: 1). Conclusions This is the first large multicenter study to specifically report the effectiveness of BsAbs in real-world for R/R tiNHL and shows that the results are in keeping with clinical trial data. Acknowledging the limited sample size and follow-up, the effectiveness of this treatment in R/R tiNHL appears comparable to that in dnDLBCL and suggests that BsAbs provide an important salvage option in this challenging-to-treat population.

Cytokine induced memory-like natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The trial adhered to a 3 + 3 dose de-escalation design, with primary endpoint being safety. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partners in vivo. The primary safety endpoint was established, with dose-limiting toxicity in 1/10 patients. A transient disease control rate correlated with donor NK cell expansion, the latter occurring irrespective of IPI. The combination of CIML NK cells with N-803 and IPI was associated with increased early NK cell proliferation, contraction of Treg: Tcon, rapid recovery of recipient CD8+ T cells, and subsequent accelerated rejection of donor NK cells. CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation affecting NK cell combination therapies in clinical trials. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI. NCT04290546.

BackgroundBispecific monoclonal antibodies (BsAbs) are utilized in patients with relapsed or refractory multiple myeloma (MM) and light chain amyloidosis (AL amyloidosis) but are associated with high rates of neutropenia and infection. Granulocyte colony stimulating factors (G-CSF) offer a potential means to mitigate infection risk and maintain BsAb treatment, however their use alongside BsAbs is not well defined.MethodsThis single-center, retrospective chart review included adult patients with MM or AL amyloidosis who received teclistamab, talquetamab, or elranatamab at Dana-Farber Cancer Institute from 2022 to 2025. The primary outcome was to assess the rate of infections in patients with or without concomitant G-CSF therapy. The secondary outcomes were to compare the infection characteristics and relative dose intensities of BsAbs in patients with or without concomitant G-CSF therapy and to describe the efficacy of G-CSF therapy.ResultsInfection rates were comparable in patients that received G-CSF (60% with G-CSF vs. 41% without; p=0.055). Relative BsAb dose intensity was similar in patients that received G-CSF (95.2% with G-CSF vs. 100% without; p=0.23). G-CSF was effective in resolving grade 3 (89%) and grade 4 (75%) neutropenia, with a median time to resolution of 7 days, and same day administration with BsAb occurred in 69% of patients.ConclusionsG-CSF administration resulted in comparable infection rates and treatment intensity relative to those not receiving G-CSF. G-CSF was effective in resolving neutropenia, often permitting same-day BsAb administration. These findings support the feasibility and utility of G-CSF during BsAb therapy to minimize infection-related complications and treatment deviations.

Background: Individuals with sickle cell disease (SCD) face an elevated risk of myeloid leukemias. Recently, myelodysplastic syndrome and acute myeloid leukemia have emerged as complications of curative SCD therapies, including gene therapy and allogeneic hematopoietic cell transplantation (HCT). Leukemias arising in SCD have been reported to harbor somatic TP53 mutations, and post-HCT TP53-mutant leukemias have been traced to low-level TP53 clones detectable pre-HCT. These findings suggest that SCD itself may predispose patients to high-risk clonal hematopoiesis (CH). Prior studies of CH in SCD used sequencing methods with limited sensitivity, yielding conflicting conclusions and potentially missing small, clinically relevant clones. In this multinational cohort, we defined CH prevalence, age distribution, and mutational profiles in SCD relative to non-SCD controls and other hemoglobinopathies. Methods: We analyzed archived blood DNA from 7,283 individuals across 17 cohorts in 4 countries: 3,885 with SCD (SS, SC, Sꞵ0, Sꞵ+), 3,398 without SCD (AA, AS, AC), and 188 with beta-thalassemia. Using duplex sequencing, we identified somatic CH variants at ≥0.001 variant allele fraction (VAF), germline variants in leukemia predisposition genes, and HBB genotypes. CH was analyzed by gene and in pre-specified biological groups: DNMT3A/TET2 (DT-CH) and DNA damage response (DDR-CH: TP53, PPM1D, CHEK2, ATM). We used binomial logistic regression (age- and sex-adjusted) to compare the prevalence of CH in SCD vs non-SCD controls. Results: We detected 6,661 CH variants in 2,673 individuals (median VAF=0.002). CH occurred earlier in SCD and was more prevalent in SCD cases compared to non-SCD controls among those aged 0-19 years [10.6% (95% CI: 9.1, 12.2) vs 3.5% (2.4, 5.0); p <0.0001]. This was driven by a selectively increased prevalence of DDR-CH in SCD [SCD: 3.3% (2.5, 4.3) vs non-SCD: 0.6% (0.2, 1.5), p = 0.0012] which extended across adult age groups (20-29 years: 3.5% vs 0.9%; 30-39 years: 7.7% vs 1.8%; 40-49 years: 15.1% vs 5.5%). Within DDR-CH, PPM1D was enriched in SCD compared to controls (36.4% vs 21.8%; p<0.0001); ATM (4.9% vs 9.5%; p=0.016) and CHEK2 (26.7% vs 34.1%; p=0.03) were underrepresented; and TP53 was similar (32.0% vs. 34.7%; p=0.45). To further evaluate the onset of CH in children with SCD, we performed serial sequencing of 148 participants enrolled in the BabyHUG trial (age 0.6 to 1.4 years) with follow-up samples obtained between 3 and 11 years of age. We detected CH, including DDR-CH, in 4.7% of children at baseline, all of which persisted in subsequent samples. Among those without CH at baseline, 3.9% developed incident CH during follow-up. In contrast to DDR-CH, DT-CH prevalence was higher in SCD among the youngest population [0-19: 6.4% (5.2, 7.7) vs 2.5 (1.5, 3.9), p<0.0001] but progressively decreased with advancing age relative to non-SCD controls. Among older individuals, (age ≥50 years), the prevalence of DT-CH was significantly lower in those with SCD than in those without SCD [54.4% (47.7, 61.0) vs 76.9% (74, 79.6), p<0.0001]. To determine whether sickle cell trait also had increased CH prevalence, we compared individuals with AA to those with AS/AC genotypes. CH prevalence was not higher in AS/AC compared to AA: overall CH (OR 1.01, p=0.95), DDR-CH (OR 0.99, p=0.50), DT-CH (OR 0.92, p=0.38). Then, to evaluate whether the association of SCD with early-onset CH was generalizable to other beta hemoglobinopathies, we analyzed the CH prevalence in pediatric beta-thalassemia patients (n=166). CH prevalence in beta-thalassemia was similar to AA controls (OR 1.37, p=0.49) and lower than SCD (OR 0.41, p=0.027). We observed no DDR-CH in beta-thalassemia. The prevalence of pathogenic/likely pathogenic germline variants in leukemia predisposition genes, such as DDX41, TERT, GATA2, and RUNX1 was similar across all evaluated HBB genotypes.Conclusions: Using deep targeted sequencing, we demonstrate that SCD is associated with a predisposition to early onset high-risk CH. Individuals with SCD exhibit markedly increased prevalence of DDR pathway mutations compared to controls, with the earliest clones detectable in infancy. This precocious DDR-CH is specific to SCD and not observed in individuals with sickle cell trait or beta-thalassemia. These findings provide a plausible mechanistic basis for the elevated relative risk of myeloid leukemias in SCD and therapy-related leukemias as a complication of curative therapies.

BACKGROUND:Recent interest in leveraging external data for clinical trial design and analysis in glioblastoma has raised questions on the identification of appropriate data to use as external controls for future trials. We perform a comprehensive analysis assessing candidate sources of external data and comparing clinical trial and real-world datasets in newly diagnosed glioblastoma. METHODS:Individual patient-level data (PLD) from several clinical trials, a large academic institutional database and a registry (National Cancer Database) were used for analysis of patients receiving standard of care radiation with concurrent and adjuvant temozolomide. Data summaries from randomized trials 2012-2022 were analyzed to account for trials without available PLD. Multivariable modeling was employed to compare survival across datasets. RESULTS:In total, 8 datasets with PLD for 3061 patients with newly diagnosed glioblastoma treated with standard chemoradiation were analyzed. Patients on trials were younger (age < 60:64% vs. 48%, p < 0.001) and had higher KPS (KPS≥90:58% vs. 48%, P < .001) compared to non-trial patients. Patients in clinical trials exhibited inferior survival relative to non-trial patients (HR 1.30,95%CI 1.13-1.48, P < .001) after adjustment for age, sex, KPS, extent of resection and MGMT methylation status. In assessment of data summaries of 19 randomized trials, there was no detectable time-trend toward improved outcomes 2012-2022. CONCLUSIONS:In newly diagnosed glioblastoma patients treated with standard of care chemoradiation, there were significant differences between trial datasets and real-world datasets but no evidence of a trial effect benefit from trial participation. After adjustment of relevant covariates, there was no evidence of temporal drift of improved survival over the last decade.

Background Combination therapy with bendamustine and rituximab (BR) is a safe and effective front-line regimen in patients with follicular lymphoma (FL) (Rummel, Lancet 2013; Flinn, Blood 2014). Long-term data regarding the outcomes of FL patients treated with BR have largely been limited to randomized trials, and there is limited insight into the outcomes and prognostic factors of patients treated off of clinical trials with this regimen. Methods We retrospectively identified consecutive adult patients with FL (grades 1-3A) who were treated at Dana-Farber Cancer Institute with front-line BR from January 1, 2013 to June 1, 2024. Baseline demographic, clinical and radiographic characteristics were collected from the medical records. Progression free survival (PFS), overall survival (OS), and cumulative incidence of histological transformation (CIHT) were calculated using standard definitions from time of treatment start, with death considered a competing cause for CIHT. Response outcomes and other categorical variables were tested for association with continuous and other categorical baseline variables using Wilcoxon rank-sum (or Kruskal-Wallis for three or more groups) or Fisher's exact tests, respectively. Results A total of 194 patients were identified. The median age of the cohort was 61 years (range 27-91), and 52% of patients were male. More than half (54%) of patients presented with stage IV disease (37% with stage III), and 86% of patients had grade 1-2 FL. The median Ki-67 and largest SUVmax at diagnosis were 15% (interquartile range [IQR] 10-30%) and 10.0 (IQR 7.5-15.1), respectively. 33 patients (17%) had a reduction in bendamustine dosing with advanced patient age being noted as the most common reason for modification. Among patients receiving dose modifications for advanced age, 10/13 (77%) were empirically given reduced-dose bendamustine in cycle 1. N patients (86%) received all 6 planned cycles of BR. 167 pts (36%) received growth factor support during treatment of which 84% was given as primary prophylaxis. Patients receiving primary prophylaxis were generally older with a median age of 66 years. 22% of patients received maintenance rituximab (median of 10 maintenance cycles). At the end of treatment, 151 patients (78%) underwent repeat PET/CT evaluation. Among these patients, the overall (ORR) and complete response (CR) rates were 89% and 80%, respectively. Among 33 patients who underwent evaluation with CT, the ORR and CR were 90% and 70%, respectively. With a median follow-up of 65.1 months, the median PFS was 66.9 months, the median time-to-next-treatment (TTNT) and the median OS were not reached. The 6-year TTNT and OS were 56% (95% confidence interval [95% CI] 48-64%) and 78% (95% CI 70%-84%), respectively. There were 5 deaths potentially related to treatment, all due to infection. 42 patients (22%) experienced disease progression within 24 months (POD24), of whom 27 (64%) had biopsy-proven evidence of histologic transformation at the time of progression.The CIHT for total cohort at 2 years and 6 years were 13% and 17%, respectively. In univariate analysis, factors associated with worse PFS included age (hazard ratio [HR] 1.24 per 10-year increase, 95% CI 1.02-1.49), elevated LDH (HR 4.69, 95% CI 2.64-8.33), SUVmax (HR 1.04 per 1-unit increase, 95% CI: 1.01-1.07), and reduction in cycle 1 bendamustine dose (HR 3.05, 95% CI: 1.85 to 5.02) by Cox regression. Elevated LDH (HR 2.72, 95% CI: 1.05 to 6.70) was associated with increased risk of transformation. We additionally examined the impact of elevated SUVmax at baseline with a cutoff of 15 based on prior literature (Rossi, Haematologica 2020), which was associated with numerically shorter PFS (median 33.3 months vs. 83.8 months, p=0.20), shorter time-to-next-treatment (median 34.1 months vs. 103.9 months, p=0.04), and increased CIT at 2 years (23% vs 6%) and 6 years (37% vs 11%) in comparison to patients with SUV≤15 at baseline (p<0.01). Conclusions This represents one of the largest real-world analysis of outcomes of patients with FL treated with frontline BR. These data redemonstrate BR is an effective first-line regimen with favorable long-term results. Notably, an elevated baseline SUVmax was associated with shorter PFS and increased risk of transformation in line with prior analysis of FL patients (Strati, Haematologica 2019), which suggest a subset of patients that may benefit from consideration of alternative therapeutic strategies.