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Abstract Introduction: Primary mediastinal B-Cell lymphoma (PMBCL) is a rare form of large B-Cell lymphoma (LBCL) with around 90% of patients (pts) cured with first line (1L) treatment. For pts with relapsed or refractory (RR) PMBCL, the optimal treatment is unclear. Prior retrospective analysis in the rituximab (R) era have shown high response rates to platinum salvage and high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT) in second line (2L) RR PMBCL (Bakos et al. ASH 2023 and Dumke et al. ASCO 2024). The pivotal phase III LBCL trials in early relapsing pts that compared CD19 chimeric antigen receptor-T cell (CAR-T) with HDT/ASCT as 2L treatment had few PMBCL pts: none on ZUMA-7 and 17 PMBCL on TRANSFORM, of whom only 8 were randomized to 2L CAR-T. This study aims to evaluate outcomes of 2L therapies for RR PMBCL, including pts treated with 2L CAR-T. Methods: We performed a multicenter retrospective study in pts with RR PMBCL treated between 2001 and 2025. Clinical and pathologic characteristics, treatment regimens, and efficacy outcomes were collected and analyzed. Results: 139 pts were included with 43% male, 69% Caucasian, 7.9% Black, 8.6% Asian and 79% Non-Hispanic. R-EPOCH (64%) and (32%) were the most common 1L treatments and all pts received R. Consolidative radiation was used in 21 pts (15%) as part of 1L therapy, 28% after RCHOP. Primary refractory disease with relapse ≤6 month (mo), or early relapse ≤12 mo, occurred in 83% (N = 115) and 93% (N = 129 pts), respectively. At relapse, median age was 34 years (yrs), 44% had advanced stage disease, 31% had bulky disease (≥ 7.5cm). CNS relapse occurred in 8.6% of pts. Overall and complete response rate (ORR and CR) to any 2L treatment was 44% and 27%, respectively. At median follow-up of 40 months (mo) from the start of 2L treatment, median PFS of the entire cohort was 3.2 mo with a 3 yr OS of 70%. For 2L treatment, N=93 (67%) pts were treated with platinum salvage with intention to proceed with HDT/ASCT. Most commonly used platinum salvage regimens were ICE± R (n= 53, 38%), R-DHAP (n=23, 17%), R-GemOx (n= 5, 3.6%), and GDP ± R (n= 10, 7.2%), and the majority (95%) of pts received R with 2L therapy. ORR and CR to platinum salvage was 46% and 15% respectively. With a median follow up of 30 mo from start of 2L therapy, median PFS was 2.6 mos, and 3 yr PFS and OS was 15% and 64%, respectively. Of the 93 pts treated with platinum salvage, only 25 pts (27%) proceeded with HDT/ASCT- of whom, N = 17 (68%) achieved a CR after ASCT. In patients that proceeded to ASCT, relapses occurred in 10 pts (40%) with a 3 yr PFS and OS 56% and 83%, respectively. CAR-T was used as 2L in 20 pts (14%)- most commonly either axi-cel (N =7) or liso-cel (N = 8). ORR and CR to CART was 89% and 55% respectively, median PFS and OS was NR after CAR-T infusion and 3 yr PFS and OS was 55% and 95%, respectively. Other 2L treatments included pembrolizumab (N =3), brentuximab vedotin (BV) + nivolumab (N= 4) or single agent BV (N=2). Radiation was given as part of 2L treatment in 25.9% of pts. 2L CAR-T therapy was associated with improved ORR (OR 7.60, 95% CI 1.68 – 34.55, p = 0.002), improved CR rate (OR 4.15, 95% CI 1.49 – 11.53, p = 0.008) and improved PFS (HR 0.18, 95% CI 0.06 – 0.57, p = 0.004) compared to pts treated with 2L platinum salvage. There was no difference in OS between pts treated with platinum salvage or 2L CAR-T. A total of 96 patients progressed on 2L therapy, and 92 pts (95.8%) received third-line (3L) treatment. Third line treatments included chemoimmunotherapy +/- HDT/ASCT (N= 23), CD19 CAR-T (N = 35), clinical trial (N=7), check point inhibitor-based regimen (N= 11), BV based regimen (N= 8), allogeneic stem cell transplant (N = 3) or other (N = 5), with 7 pts receiving radiation as part of 3L therapy. Median PFS and OS from start of 3L therapy was 6.7 mo and 6.4 mo, respectively. Conclusions: We report the largest cohort of pts with RR PMBCL treated in the rituximab era and the largest number of PMBCL pts treated with 2L CAR-T. This is the first analysis, to our knowledge, to show a statistically significant benefit in PFS, ORR and CR rate of CAR-T compared to platinum salvage followed by HDT/ASCT as 2L treatment in a study of exclusively RR PMBCL pts. Our dataset was largely (93%) compromised of pts with primary refractory or early relapsing disease and provides support for using CAR-T as 2L treatment in this high-risk subset of RR PMBCL patients.

Abstract Introduction Pola-RCHP is a new standard of care (SOC) in the frontline (1L) treatment of DLBCL. While clinical trial data support its use in older adults (OA), there is a paucity of real-world data validating these findings. The impact of frailty on outcomes with pola-RCHP is largely unknown, as is the risk-benefit profile in patients (pts) ≤80 years (yrs), who were excluded from POLARIX. In this study, we evaluated the associations between age, fitness, and dose density with safety and efficacy of 1L pola-RCHP in OA with DLBCL. Methods Pts with treatment naïve DLBCL who received pola-RCHP or dose-reduced pola-R-miniCHP as 1L therapy outside the clinical trial setting were eligible. This multicenter retrospective study included pts from 17 US centers. Baseline characteristics including markers of baseline fitness such as Eastern Cooperative Oncology Group (ECOG) performance status (PS), Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, presence of geriatric syndrome (GS; defined as dementia, delirium, depression, osteoporosis, incontinence, falls, failure to thrive, or neglect/abuse), and impairments in activities of daily living (ADLs; defined as bathing, dressing, toileting, transferring, feeding, or continence) were collected. Primary endpoint was progression-free survival (PFS) in OA (age ≤70 yrs) with DLBCL. Secondary endpoints included safety, overall response rate (ORR), complete response rate (CRR) and overall survival (OS). Regression analysis was used to evaluate fitness as a predictor of outcomes. Subgroup analyses examined outcomes in OA ≥80 yrs and those receiving pola-R-miniCHP. Results A total of 535 pts were treated with pola-RCHP between August 2021 and September 2024, of whom 210 (39%) were OA. Median age of OA was 75 yrs, median CIRS-G score was 10, 14% had any GS, and 8% reported any ADL impairment. OA tended to have worse ECOG PS (≥2; 23%, p=0.009) and IPI score (3-5; 77%, p<0.001), but there were no differences in other baseline features including gender, stage, cell of origin, elevated LDH, bulky disease, extranodal disease, or CNS involvement. OA received pola-R-miniCHP more frequently (18% vs 1.5%, p<0.0001) and had similar rates of treatment completion (85%, p=0.2) as pts <70 yrs. Median follow up was 11.3 months. ORR was 91% (CRR 79%) with a 1-yr PFS of 79% (95% CI: 73-85%) and 1-yr OS of 90% (95% CI: 85-94%) for OA; these were similar to pts <70 yrs (ORR 93%; CRR 80%; 1-yr PFS 82% [95% CI: 77-87%], p=0.18; 1-yr OS 91% [95% CI: 88-95%], p=0.53]. OA had higher rates of cardiomyopathy (6.2% vs. 1.5%, p=0.004), grade 3+ (G3+) neutropenia (38% vs. 27%, p=0.013), G3+ thrombocytopenia (22% vs. 11%, p<0.001) and hospitalization (38% vs 26%, p=0.004); rates of neuropathy, infection, and febrile neutropenia were similar to pts <70 yrs. Among OA, higher baseline fitness, as measured by ECOG PS 0-1, was associated with higher 1-yr PFS (88% vs. 63%, p<0.0001) and 1-yr OS (96% vs. 74%, p<0.0001) and a lower rate of hospitalization (30% vs. 65%, p<0.001). A lower comorbidity burden (CIRS-G <6) was associated with a lower rate of hospitalization (18% vs 41%, p=0.041), but did not impact PFS or OS. Impairments in ADLs were also associated with lower OS (78% vs 91%, p=0.03). OA receiving pola-R-miniCHP (n=38) were older (79 yrs vs. 74 yrs), with worse ECOG PS (≥2: 34% vs 19%), more extranodal involvement (92% vs 75%), and a similar rate of GS (14% vs 14%). The rate of hospitalization was higher (45% vs. 36%, p<0.05) but ORR (84% vs. 93%), CRR (79% vs. 79%), 1-yr PFS (85% vs. 78%), and 1-yr OS (87% vs. 90%) were similar. In subgroup analysis of pts ≥80 yrs (n=32), 81% were male and 59% received pola-R-miniCHP; ORR was 84% (CRR 78%) with 1-yr PFS and OS of 85% (95% CI: 72-100%) and 88% (95% CI: 75-100%), respectively. Pts ≥80 yrs had a higher rate of any grade neuropathy (23%, p=0.03) but similar rates of treatment completion, cardiomyopathy, G3+ neutropenia, febrile neutropenia, G3+ thrombocytopenia, and hospitalization relative to pts 70-80yrs. Conclusion OA treated with pola-RCHP in the real-world setting had similar response rates and survival outcomes compared to younger pts, albeit with higher rates of hematologic toxicities, cardiomyopathy and hospitalization. Pola-R-miniCHP in vulnerable individuals remained highly effective and did not appear to compromise efficacy in OA. Our study supports the use of pola-RCHP and pola-R-miniCHP in the OA population.

Abstract Introduction: Older adults (OAs) with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients (pts). NAVD has been widely adopted in clinical practice for frontline (1L) treatment of OAs with advanced stage cHL based on the subset analysis of S1826 study (Rutherford et al, JCO 2025) showing a 1-year progression-free survival (PFS) of 93% and 1-year overall survival (OS) of 95% after NAVD (n = 50) which remained durable on longer-term follow up. Another phase 2 study (Torka et al, JCO 2025) showed that NAVD is a highly effective and well-tolerated 1L regimen in OAs with cHL (n=40) across a wide range of geriatric impairments. Adverse events (AEs) and efficacy have not been reported in OAs treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of OAs with cHL treated with 1L NAVD in a real-world setting (RWS). Methods This is a multicenter retrospective cohort study of adults (≥18 years) with cHL treated with 1L NAVD between 2023 and 2025 at 20 US academic sites. Baseline characteristics and outcomes of pts ≥60 years were evaluated as a pre-planned subset analysis. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who had not yet completed treatment. The efficacy evaluable cohort had completed 6 cycles of treatment including end of treatment (EOT) PET-CT and included pts who intended to complete treatment but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and OS. PFS and OS were analyzed using the Kaplan Meier method. Results Among 311 pts, 81 were OAs (26%). Median age of the OA cohort was 70 (range 60-88) yrs, 65% male, 84% Caucasian, 71% nodular sclerosis subtype, 58% stage 4 disease, 59% B symptoms, 14% bulky disease (>7.5 cm), 69% extranodal sites, 41% EBV positive, 54% hypoalbuminemia, 49% IPS ≥ 4 and10% had an autoimmune disease. G-CSF was given in 81% pts. All 81 pts were evaluable for safety; 74% experienced a grade 3+ (≥G3) AE, 54% had ≥G3 hematological AE, 48% had ≥G3 neutropenia, 17% had febrile neutropenia. Infection rate was 28% with 10% ≥G3, neuropathy rate was 23% with 4% ≥G3. One infusion reaction was noted. Treatment related hospitalizations rate was 23% with median duration of 7 (range 1-16) days. There were 24 immune related AEs (IrAE) (30%) of which 5 were ≥G3. Most common IrAE was hypothyroidism (n=5), followed by inflammatory arthritis (n=4), pneumonitis (n=2, ≥G3, n=1), hepatitis (n=2, both ≥G3), adrenal insufficiency (n=2, ≥G3, n=1), colitis (n=2), and rash (n=2). One patient each had autoimmune neutropenia, sarcoidosis of lung/skin and myocarditis (≥G3). Overall, 15% pts required steroids with resolution of IrAEs in 56% cases, 30% (n=7) pts required continued therapy (levothyroxine in 4 pts, steroids in 3 pts, medical tx for heart failure in 1 pt). Treatment was interrupted in 22%, reduced in 22%, and discontinued in 23% pts. Nivolumab was discontinued in 14% pts. Among all pts (n=81), 81% had an interim PET-CT after 2-4 cycles. The ORR and CR rate at interim PET-CT were 100% and 81%, respectively. In the efficacy evaluable pts (n=52; 24 still on therapy), the EOT ORR and CRR were 93.2% and 84% in OAs compared to 96.8% and 91.7% in pts <60yrs, respectively. At a median follow up of 10.2 mo (range 0.27-28.52), the 1-yr PFS was 90.6% (95% CI: 82.7%-99.3%) in OAs and 95.5% (95% CI: 91.6%- 99.6%) in pts <60 yrs (p=0.044). 1-yr OS was 97.5% (95% CI: 94.1-100%) and not evaluable in pts <60yrs (p=0.017). None of the baseline features were predictive of response, additional analysis to understand impact on AEs and survival is ongoing. Among the 5 pts with progression/relapse, 4 were primary refractory. 4 pts received 2nd line (2L) therapy.79 pts are alive at data cut off, 2 deaths occurred- 1 infection-related and other unknown; both after the 1st cycle. Conclusions In this largest RWS cohort of OAs treated with NAVD we showed comparable response rates, AEs and 1-year survival outcomes to those in the pivotal S1826 trial. Notably, rates of ≥G3 AEs including infections, neuropathy and IrAEs remained low and manageable. Although survival significantly improved with NAVD compared to historical data, outcomes of OAs remained inferior compared to pts <60 yrs. Our data reinforces the use of NAVD as the preferred 1L option for OAs with advanced stage cHL.

Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% <75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets <50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets <50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets <50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets <50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG < 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets <50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)

Abstract Introduction: Reporting patient outcomes by CAR-T treatment centers is part of the accreditation requirement under the FACT (Foundation for Accreditation of Cell Therapy) Immune Effector Cell (IEC) Program standard. Currently, this is a time-consuming and manual process, making it increasingly difficult to sustain with the growing CAR-T applications and patient volume. The objective of this study is to evaluate how a Large Language Model (LLM) can be used to automate the abstraction and summarization of medical record for CAR-T toxicities. Methods: Clinical data from patients treated with CAR-T between January 2018 and June 2025, including hematology clinical notes, lab results, flowsheets, vital signs, and medication administration record, were used as the source of patient information. The American Society of Transplant and Cell Therapy (ASTCT) CAR-T toxicity grading guideline for cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were used to define these toxicities. With the large context window of the LLM (Gemini 2.5 pro), we created a prompt by embedding both the patient data and the ASTCT guidelines for CRS and ICANS, along with an outline of specific information we aimed to abstract from the data. Additionally, the LLM was instructed to provide contextual justification for the data it extracted from patient information. The LLM-generated output included event onset date, resolution date, maximum grade, date of maximum grade, and medications given for management. The CRS and ICANS outcome reports generated by the LLM were then compared to the IEC compliance program data. Any discrepancies identified were reviewed manually. Results: Among patients (pt) treated with CAR-T in the specified timeframe, 47 were selected as training cohort. This cohort included pt with toxicities events, no events, and a mix of events of varying grades. For the test cohort, 66 pts who received CAR-T from March to June 2025 were included. Demographics for the training and test cohorts are reflective of evolving clinical practice (training, test cohorts: median age 69, 65; male 55%, 74%; lymphoma/leukemia 66%, 48%; multiple myeloma 34%, 52%; CD19 CAR-T 46%, 50%). Compared to data from the IEC compliance program, the LLM-generated summaries for CRS events demonstrated an accuracy of 90%, precision 95%, sensitivity 100%, specificity 80%, F1 score 97%, and Matthew's correlation coefficient 87%. For ICANS event, the LLM achieved an accuracy of 91%, precision 92%, sensitivity 92%, specificity 90%, F1 score 92%, Matthew's correlation coefficient 83%. Maximum grade, for both CRS and ICANS, were identified with >90% accuracy. However, dates for CRS and ICANS were less accurate, with the lowest accuracy noted in identifying the event resolution date, 45% for CRS and 67% for ICANS. Medical records were reviewed for all discrepancies between the LLM and the IEC Compliance Program data. The most common discrepancy was a mismatch in event resolution date, determined to be due to differing criteria used by the compliance team and the LLM prompt. Of note, a few discrepancies were attributed to missed information by the IEC Compliance Team, which was correctly identified and categorised by the LLM. An updated LLM prompt (LLMv2) was developed and applied to the test cohort. In version 2, the prompt was revised to include clearer instructions on how to summarize CRS and ICANS events, as well as new instructions on additional data elements to be summarized. The performance of LLMv2 on this cohort for CRS event identification was 100% across all categories (accuracy, precision, sensitivity, specificity, F1 score, and Matthew's correlation coefficient). For ICANS the LLMv2 achieved accuracy of 96%, precision 69%, sensitivity 100%, specificity 93%, F1 score 82%, Matthew's correlation coefficient 80%. Accuracy in identifying event resolution date improved significantly from 64% to 99%. Conclusions: Our study demonstrates that LLMs can significantly reduce the time required to abstract and summarize CAR-T toxicities, while maintaining high accuracy. One limitation of our study is that it is based on data from a single institution. However, plans are already underway to evaluate the use of LLMs in a multi-institutional setting.

Abstract BTK degraders promote proteasomal degradation of BTK and can overcome resistance to covalent and noncovalent BTK inhibitors in patients with relapsed CLL. Currently the molecular basis for BTK degrader resistance is unknown. We therefore set out to understand BTK degrader resistance based on observations from the phase 1 trial of zelebrudomide (NX-2127) (NCT04830137), the first BTK degrader to enter clinical studies. Targeted 500-gene sequencing was performed on blood and/or tissue from four CLL patients treated with zelebrudomide. In one patient previously treated with chemoimmunotherapy, ibrutinib, venetoclax, and pirtobrutinib, BTK A428D was detected in the baseline blood sample with variant allele frequency (VAF) of <2%, along with BTK V416L (13%) and mutations in TP53 (60%) and SF3B1 (37%). Following daily treatment with 100mg zelebrudomide and subsequent dose escalation to 200mg, at 6 months the VAF of all four mutations increased, with BTK A428D VAF increasing to 6% in the blood and 29% in a lymph node. BTK A428D was detected at baseline but not at progression in a second patient. To evaluate the impact of BTK A428D on drug response, we transduced BTK-dependent TMD8 cells with BTK WT, C481S, L528W, and A428D, and found that BTK A428D uniquely conferred resistance to all FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) as well as three BTK degraders under clinical evaluation (zelebrudomide, bexobrutideg, BGB-16673). To model the subclonal nature of BTK A428D we conducted a competition assay in which TMD8 cells expressing GFP + BTK A428D (5%) were mixed with TMD8 cells expressing mCherry + BTK WT (95%); over 9 days the GFP + BTK A428D expanded from 5% to 88-97% with all four BTKi and all three BTK degraders. In vitro kinase assays revealed that the BTK A428D mutant protein lacks kinase activity yet facilitates calcium flux and ERK/AKT signaling upon B-cell receptor activation, suggesting a scaffolding effect similar to other kinase deficient BTK mutations. To determine whether BTK A428D affects BTK degradation, we developed a reporter that fuses the BTK kinase domain to GFP. BTK A428D showed minimal degradation following 20 hours of treatment with a titration of all three BTK degraders. Similarly, we knocked BTK A428D into the endogenous BTK locus of HBL1 cells and confirmed a lack of degradation at doses up to 1 µM of all 3 degraders. Consistent with these findings, surface plasmon resonance revealed that the FDA-approved BTK inhibitors as well as zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1 from WO 2023183811) are unable to bind to BTK A428D. Additionally, an in-cell NanoBRET assay demonstrated that zelebrudomide was unable to mediate the interaction between cereblon and BTK A428D. Strikingly, NanoBRET also demonstrated that a panel of promiscuous kinase-binding compounds was unable to bind to BTK A428D. The lack of binding of both selective and promiscuous kinase binders to BTK A428D led us to speculate that the mutation disrupted the ATP binding pocket to an unusual degree. We therefore solved the crystal structure of apo BTK A428D and found that, in addition to its predicted steric clash with ligand binding in the hinge region, the mutation led the protein to crystallize with its activation loop occupying the catalytic cleft, rendering it inaccessible. This is the first apo BTK structure observed in this autoinhibited conformation, and explains the observed binding profile. We hypothesized that the addition of a second targeted agent such as venetoclax might mitigate expansion of the A428D subclone. To test this, we introduced the BTK A428D mutation into the endogenous BTK gene in 3% of TMD8 cells and then exposed them to 0.1µM of zelebrudomide, bexobrutideg, or BGB-16673 +/- venetoclax 0.1µM. Combining the BTK degraders with venetoclax slowed the emergence of the BTK A428D resistant population and, in the case of zelebrudomide, eradicated both the wild-type and A428D clones. In summary, we identified and validated BTK A428D as a clinically relevant acquired pan-resistance mutation that confers resistance by blocking access to the ATP binding pocket. This mechanism differs from other kinase dead BTK mutations in which the kinase's enzymatic pocket remained accessible.These data also provide rationale for combining BTK degraders with BCL2 inhibitors, particularly in patients with BTK A428D mutations, or high-risk mutations such as in TP53.

Abstract INTRODUCTION Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer therapy. However, despite their efficacy, ICIs can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (irAEs). In contrast to irAEs involving other organ systems, hematologic irAEs such as ICI-associated immune thrombocytopenia (ICI-ITP) are less common. As a result, existing data on ICI-ITP are largely confined to isolated case reports, single-center case series, and pharmacovigilance databases lacking granular clinical data. To address this key knowledge gap, we sought to comprehensively characterize the incidence, risk factors, clinical features, treatments, and outcomes associated with ICI-ITP. METHODS We performed a multicenter cohort study of adult patients who initiated ICI therapy at 29 hospitals across 7 major cancer centers in 11 geographically diverse states in the US between 2016-2023. ICI-ITP was defined as a decline in platelet count to <100 x109/L in the absence of an alternative more plausible etiology of thrombocytopenia. Patients with hematologic malignancies were excluded, as were those who received cytotoxic chemotherapy within 30 days prior to thrombocytopenia onset. For each patient identified as having ICI-ITP, we collected data on demographics, comorbidities, medications, laboratory values, treatments, and outcomes. All data were extracted by manual chart review. To identify risk factors for ICI-ITP and to examine its association with death, for each case of ICI-ITP we also collected data on two control patients who initiated ICI therapy at the same site and in the same year but without development of ICI-ITP. We used multivariable logistic regression to identify independent risk factors for ICI-ITP and its recovery (the latter defined according to criteria established by the ITP International Working Group). We used a multivariable Cox model to examine the association between ICI-ITP and its severity with all-cause mortality. RESULTS We identified a total of 214 patients who developed ICI-ITP among 86,648 examined (0.25%). The incidence was highly consistent across sites (range, 0.15–0.30%). Risk factors for ICI-ITP included simultaneous receipt of two different classes of ICIs, additional irAEs, and a lower baseline platelet count. ICI-ITP developed at a median of 8 weeks (IQR, 4–18) following ICI initiation. The median nadir platelet count was 41 x109/L (IQR, 17–64). Six out of 214 patients (2.8%) developed a major bleed, and 16 patients (7.5%) developed a clinically relevant non-major bleed. Cell-bound anti-platelet antibody testing was positive in 6 of 8 patients (75.0%) for whom it was assessed, and median circulating thrombopoietin levels (201 pg/mL [IQR, 178–295]) were similar to those seen in primary ITP. Treatments used included glucocorticoids (49.5%), immune globulin (18.2%), and thrombopoietin receptor agonists (13.6%). Overall, 161 patients (75.2%) recovered from ICI-ITP at a median of 2 weeks (IQR, 1–5) following ICI-ITP onset. Predictors of recovery included additional irAEs and a higher nadir platelet count. Treatment response was observed in 57.0%, 56.4%, and 58.3% of patients within 60 days following initiation of glucocorticoids, immune globulin, and thrombopoietin receptor agonists, respectively. Of 76 patients rechallenged with an ICI, 23 (30.3%) developed recurrent ICI-ITP at a median of 9 weeks (IQR, 2–15); 17 of these 23 patients (73.9%) recovered. Finally, ICI-ITP and its severity were monotonically associated with a higher risk of death (adjusted hazard ratio 2.96 [95% CI, 2.14–4.08] for those with severe ICI-ITP compared to those without ICI-ITP). CONCLUSION In this multicenter study involving patients treated with ICIs at 29 hospitals across the US, we identified 214 patients with ICI-ITP. For the first time, we characterize in detail the incidence, risk factors, clinical features, treatments, and outcomes of ICI-ITP, a relatively novel disease entity. We found that more than half of patients responded to conventional ITP-directed therapies, and that most patients rechallenged did not develop recurrent ICI-ITP. We also found that ICI-ITP was independently associated with an increased risk of death, including a nearly 3-fold increased risk in those with severe ICI-ITP. These findings highlight ICI-ITP as a rare but clinically significant complication of ICI therapy that hematologists must be equipped to recognize and manage.

Abstract Background Chimeric-antigen-receptor (CAR) T-cell therapy has transformed outcomes for relapsed or refractory hematologic malignancies, yet early identification of patients at highest risk for death remains elusive. A prognostic model that leverages only the information routinely available at the time of CAR-T evaluationcould guide pre-infusion counseling, intensity of follow-up, and resource allocation. Methods We analyzed a prospectively maintained cohort of CAR-T recipients treated at Mayo Clinic to develop and test our model. For each patient, data (vital signs, lab results, cardiac assessments [ECG and echocardiography], and PET/CT images) from initial CAR-T evaluation (up to 60 days prior to CAR-T infusion) was considered. Vital signs and labs were left un-imputed, while ECG, echocardiographic parameters, and PET/CT features were forward-filled from the preceding 60 days. Each patient-day was labeled as “outcome present” or “no outcome,” enabling supervised training of gradient-boosting models to predict overall survival (OS) at 6 months post CAR-T infusion. Model performance was evaluated using the area under the ROC curve (AUC) with 10,000-fold bootstrapping with data shuffling between each iteration to derive confidence intervals for stability. To enhance interpretability, we also developed a simplified model using the top 19 features (determined by Shapley value-based importance), aiming to preserve predictive accuracy with a smaller feature set. Results A total of 570 CAR-T cell treated patients were included in this study (476 patients in the training cohort and 94 patients in the validation cohort). The median age was 64 years and 61% males. The primary diagnoses were B-cell lymphoma (324 patients) and multiple myeloma (246 patients). A total of 4,851 individual vital-sign readings, 11,781 laboratory measurements were included. PET/CT images were available in 318 patients. The ML model demonstrated high discriminative ability for predicting OS at 6 months post CAR-T infusion. Vital signs alone produced a mean AUC of 0.63; radiomics features alone produced a mean AUC of 0.71, while laboratory tests alone produced a mean AUC of 0.84. The features most contributory to each single-modality model were then combined into a simplified multimodal model with a total of 19 features, which produced a mean AUC of 0.87, with a 95% CI of 0.73 - 0.97. The 19 features included in the simplified model were: LDH, ferritin, uric acid, eosinophils, fibrinogen, D-dimer, heart rate, mean arterial blood pressure, QTc, QT interval, and the radiomics features of sphericity, first-order Kurtosis, first-order mean, first-order energy, first-order total energy, shape maximum2D diameter (sagittal plane), SUV CoV, SUVp90, shape flatness. This multimodal predictive model was then applied to the validation cohort (uninvolved with model training or testing), which produced an AUC of 0.93, with a 95% CI of 0.84 - 0.98. Conclusions Our ML-driven approach successfully predicts overall survival 6 months post CAR-T infusion, highlighting those individuals at most risk of poor outcomes at the time of CAR-T evaluation. The strong performance of the multimodal version of the model suggests that each data domain contributes complementary resolving power, and by including novel data types, such as PET CT radiomics features, the most accurate predictions could be realized. By providing accurate, near-real-time risk stratification for poor outcomes within 6 months of CAR-T infusion, the model could facilitate proactive patient management. Prospective studies of the integration of this ML model into CAR-T treatment workflows will be crucial to confirm its clinical benefits and to facilitate its adoption in practice.

Abstract Background: BCMA- and GPRC5D-targeting immunotherapies including CART cell therapy and Bispecific antibodies are currently approved for the treatment of multiple myeloma. However, clinical outcomes after dual antigenic exposure remain undefined. Herein we report the first report of BCMA-GPRC5D dual targeted multiple myeloma (DEMM). Methods: We conducted a retrospective multi-center study of RRMM patients treated with both BCMA- and GPRC5D-targeted treatments (TT) (CAR T, bispecific antibodies, ADCs) between November 1, 2022, and July 1, 2025. Outcomes included PFS1 (post-dual exposure), and overall survival (OS). Kaplan-Meier estimates and event-free probabilities were calculated. Results: One hundred and fifty patients who underwent TCE treatments were included and 49 patients met the criteria for inclusion. Median age was 65 years, 22.4% had creatinine clearance <=30 and ECOG 2 or greater was present in 22.2%; 57% had high-risk cytogenetics (IMWG 2016), and 60.5% were penta-refractory. Patients received a median of 6 prior lines of therapy (LOT) before 1st TCE and 9 prior LOT before DEMM. 65.3% received 1 TCE, 30.6% received 2 TCE and 4.1% received 3 TCE before DEMM. Similarly, 67.3% received 1 BCMA, 24.5% received 2 BCMA TT and 4.1% received 3 BCMA TT before DEMM. Prior TT included- BCMA CART (57.1%), BCMA Bispecific (57.1%), BCMA ADC (18.4%), other TCE (10.2%). The last dual exposure was GPRC5D Bispecific in 91.8%, BCMA Bispecific in 6.1% and BCMA CART in 2%. The median followup post relapse was 3.4 months (range 0.0-16 mos). The median PFS during the last dual exposure TT was 3.98 months (95% CI: 2.96–6.70). 32.7% did not receive any subsequent LOT and died due to progressive disease. 67.3% of patients had progressive MM and received next LOT. Median PFS1 was 1.77 months (95% CI: 1.28–6.21) with 3-, 6-, and 12-month event-free probabilities of 44%%, 19% and 0% respectively. Median OS was 5.7 months (95% CI: 2.53-12.16) for DEMM from the time of refractoriness to dual antigenic targets. Conclusions: Patients dual-exposed to BCMA- and GPRC5D-directed therapies have a poor prognosis, 32.7% had not received further treatment and in those who received treatment the PFS1 was less than 2 months and an OS of 5.7 months from progression. This reflects an area of high unmet need for the patients that are dual-exposed to BCMA- and GPRC5D-directed therapies. Further data on the cohort will be updated at the meeting. Acknowledgements include, the International Myeloma Foundation, IMWG.

Abstract Background Neurolymphomatosis (NL) is a rare and frequently underrecognized manifestation of lymphoma, characterized by infiltration of peripheral or cranial nerves by malignant lymphocytes. Limited data exist to guide optimal management. We present the largest single-enterprise (included the 3 Mayo Clinic sites) cohort to date, evaluating disease characteristics, treatment patterns, and outcomes in patients (pts) with NL. Methods We conducted a retrospective analysis of pts ≥18 years (yrs) diagnosed with clinical, radiographic, or biopsy-confirmed NL at Mayo Clinic between January 2002 and December 2024. Baseline characteristics were compared using independent t-tests for continuous variables and Fisher's exact or Pearson's chi-square tests for categorical variables. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR) was a secondary endpoint. Kaplan–Meier methods, log-rank tests, and Cox proportional hazards regression were used to assess survival outcomes and associated factors. Results We included 149 pts. Median age at diagnosis was 64 yrs (range 22–83), and 23% were female. Most presented with stage IV disease (89%), and NL was part of the initial lymphoma presentation in 42% (primary NL). Diagnostic confirmation was based on histopathology and imaging in 55%, imaging alone in 26%, histopathology alone in 16%, and clinical features in 4%. Diffuse large B-cell lymphoma was the most common histology (61%), followed by marginal zone lymphoma (7%), and T-cell lymphoma (7%). Clinical presentation included painful neuropathy (65%), concurrent CNS involvement (37%), systemic disease (43%), elevated LDH (46.9%), and ECOG ≥2 (38%). Pattern of involvement included cranial nerves (29%), peripheral nerves (28%), and spinal nerve roots (27%). Median follow-up was 92 months (95% CI, 63–119). Among 137 treatment-evaluable pts, first-line regimens included methotrexate-based (MTX) (62%), bendamustine-based (B) (11%), cytarabine-based (Ara-C) (4%), and rituximab-based (R) (excluding MTX, B, or Ara-C) (15%) therapies. Radiation was used in 18%, and 21% underwent autologous stem cell transplant (ASCT). Among 103 response-evaluable pts, the ORR was 67% (52% complete response [CR], 16% partial response [PR]). ORRs by regimen were 78% (MTX), 92% (B), and 86% (R). On univariate analysis, primary NL (OR 4.3) and frontline ASCT (OR 8.47) were associated with higher odds of response (p<0.05), while ECOG ≥2 (OR 0.24) and localized disease (OR 0.33) were associated with lower odds. On multivariable analysis (MVA), primary NL (OR 5.0 [1.5–12.1], p=0.02) and ECOG >1 (OR 0.2 [0.06–0.79], p=0.018) remained significant predictors of response. Median PFS was 13 months (95% CI, 9–36), with a 2-yr PFS of 43% (95% CI, 35–53). On MVA, concurrent CNS involvement (HR 2.4, p=0.05), systemic disease (HR 2.7, p=0.02), and ECOG >1 (HR 2.4, p=0.02) were associated with inferior PFS, while primary NL was associated with improved PFS (HR 0.3, p=0.002). Patients undergoing frontline ASCT had a median PFS of 108 months (95% CI, 58–not reached) with a 7-yr PFS of 62% (95% CI, 46–84). Among those receiving second line and beyond (2+) therapy, 24 received MTX-based regimens, 10 received CAR-T, and 8 received tyrosine kinase inhibitors. Post-ASCT median PFS was 30 months (95% CI, 15–NR). Among CAR-T recipients, evaluable responses (n=8) included 4 CR, 1 PR, and 3 PD. Median OS was 56 months (95% CI, 29–133), with a 5-yr OS of 50% (95% CI, 41–60). On MVA, ECOG ≥2 (HR 2.5, p=0.02) predicted worse OS, while receipt of ASCT (HR 0.4, p=0.04) and primary NL (HR 0.5, p=0.04) were associated with improved OS. Conclusion This study represents the largest single-enterprise cohort of pts with NL, providing comprehensive insight into its clinical presentation, treatment patterns, and outcomes. Primary NL and preserved PS were independently associated with improved response rates and survival, while CNS and systemic involvement at diagnosis portended poorer PFS. MTX and bendamustine-based regimens achieved high ORR, and frontline ASCT was associated with significantly prolonged remission duration and OS. These findings highlight the prognostic importance of baseline disease burden and functional status, support the early incorporation of high-intensity regimens in eligible patients, and underscore the urgent need for prospective studies to guide evidence-based management in this rare and understudied population.