Citations

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Background Murine double minute 2 (MDM2) inhibitors reactivate wild-type p53 and are a promising therapy for glioblastoma, IDH-wildtype (GBM). Brigimadlin is a highly potent MDM2 inhibitor being tested in a phase 0/1 clinical trial in combination with radiation in GBM. Methods Brigimadlin pharmacokinetics, pharmacodynamics, and efficacy were evaluated in GBM patient-derived xenografts (PDXs). Results In vitro, brigimadlin impaired viability in TP53 wild-type GBM with an IC50 of 0.8-6.6 nmol/L, but sensitivity did not correlate with MDM2 amplification. In vivo, MDM2 amplification was highly correlated with efficacy. In subcutaneous PDXs, 1 or 2 mg/kg brigimadlin dosed weekly was highly effective in 2 MDM2-amplified PDXs. At 2 mg/kg, brigimadlin delayed tumor regrowth by &gt;5-fold in the MDM2-amplified PDXs compared to 1.5-fold in a non-amplified PDX. In orthotopic PDXs, efficacy was more limited, but 2 mg/kg brigimadlin enhanced the response to fractionated radiation in MDM2-amplified PDXs. Consistent with blood-brain barrier efflux limiting drug distribution, 2 mg/kg brigimadlin extended survival by &gt;5-fold in an MDM2-amplified orthotopic PDX established in Rag1−/−Abcb1a−/− Abcg2−/− mice. In pharmacodynamic studies, p53 target genes were upregulated at both subtherapeutic and therapeutic dose levels, and the extent of activation did not correlate with MDM2 status. Concentrations of brigimadlin in tumor tissue were approximately 10-fold higher in MDM2-amplified tumors, and intracellular drug levels directly correlated with drug-dependent MDM2 upregulation, suggesting target binding affects drug accumulation. Conclusions Brigimadlin is highly effective in MDM2-amplified GBM when adequate drug levels are achieved in tumor tissue. MDM2 amplification impacts both treatment efficacy and intratumoral drug accumulation.

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

Abstract Direct in vivo T cell engineering offers a new paradigm for CAR T delivery. We have evaluated several approaches to engineer lentiviral (LV) vectors capable of delivering CAR transgenes directly and selectively to T cells in vivo, within the lymphoid niche. Our goal was to develop an LV delivery platform that following intravenous administration can selectively bind and activate T cells, deliver and integrate the (CAR) transgene into genomic DNA, and drive CAR expression on the T cell surface. Further requirements were that the retargeted LV should be associated with minimal off-target transduction of tumor cells and normal host tissues and should be manufacturable at titers sufficient for human application. Our strategy for retargeting has been to modify the trimeric VSV-G protein, which is well established for efficient LV pseudotyping. Of the approaches evaluated, three retargeting platforms have proven to be effective: direct covalent display, indirect covalent display, and G-capping. Direct covalent display. This (LV-169) approach uses chimeric VSV-G protein that contains a CD3-targeting ligand displayed as a N-terminal extension of VSV-G protein that has been mutated to ablate (blind) its interaction with the LDL receptor. Chimeric and nonchimeric blinded G proteins are co- incorporated into LV particles within mixed envelopes which bind to CD3. Upon binding to cell surface CD3, the engineered particles activate T-cells and enter acidifying endosomes, whereupon they trigger membrane fusion and deliver their payloads. LV-169 displaying an anti-human CD3 scFv selectively transduced resting human T cells in PBMC cultures, in fresh human whole blood and following intravenous administration to humanized mice. In immunocompetent Cre reporter mice, surrogate vectors displaying anti-murine CD3 scFv selectively transduced lymph node resident T cells, with off-target transduction being limited to tissue-resident macrophages. To eliminate the incorporation of CAR protein into the LV-169 envelope, which can lead to highly undesirable transduction of tumor cells expressing the CAR target, we placed the CAR transgene in reverse to 5'LTR orientation, downstream of a T-cell specific promoter/enhancer. In vivo efficacy of LV-169-BCMA-CAR was demonstrated in humanized mice bearing disseminated OPM-2 myeloma tumors. Clinical translation of this construct is now underway. Indirect covalent display. In this G-protein engineering approach, a short peptide (SPY-tag) is displayed as an N-terminal extension of the LDLR-blinded VSV-G protein. The SPY-tagged LV vectors are then covalently modified to display a CD3-targeting ligand by simply mixing them at room temperature with a bifunctional fusion protein consisting of the SPY-catcher and the CD3 ligand. Under these conditions, the SPY-catcher and the SPY-tag spontaneously form a covalent isopeptide bond. The CD3 ligand-modified LV particles were shown to specifically activate and transduce T cells ex vivo within human PBMC cultures. G-capping. In the final approach, the VSV-G protein is not genetically modified. Instead, a “capping” protein crosslinker that binds directly to the unmodified G protein on preformed LV particles is used to mask their LDLR binding sites and redirect them to interact with CD3. Mixing of the CD3-targeted capping protein with traditional G-pseudotyped LV particles leads to efficient binding of the cap to the trimeric G proteins. The cap-modified LV are unable to interact with LDLR but interact efficiently with CD3. CD3-capped LV particles were highly specific and efficient in human T cell activation and transduction in PBMC cultures. The association between the G protein and the bound cap is highly stable during freeze-thaw cycles and at room temperature, a critical attribute of this platform to facilitate the manufacture of a clinically and commercially viable LV product. In summary, we have developed three translationally relevant platform technologies for the generation of LV particles capable of delivering CAR transgenes specifically and efficiently to resting niche-resident T cells after intravenous administration. Manufacturing studies are underway and, in the case of the LV-169 platform, clinical translation is already in progress.

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&lt;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&lt;0.0001) and had similar rates of treatment completion (85%, p=0.2) as pts &lt;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 &lt;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&lt;0.001) and hospitalization (38% vs 26%, p=0.004); rates of neuropathy, infection, and febrile neutropenia were similar to pts &lt;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&lt;0.0001) and 1-yr OS (96% vs. 74%, p&lt;0.0001) and a lower rate of hospitalization (30% vs. 65%, p&lt;0.001). A lower comorbidity burden (CIRS-G &lt;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&lt;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: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network blast phase registry on 240 pts reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we undertook this study through the H Jean Khoury Cure CML Consortium (HJKC3) to describe the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2025 were included. Categorical variables were compared using Chi-square test. Overall survival (OS) was calculated from time of diagnosis of CML BP to death from any cause. Event free survival (EFS) was calculated from date of best response to event (death or relapse). Results: Of the 283 pts with CML-BP, 96 (33.9%) were female and 187 (66.1%) were males. At the time of diagnosis, 183 (64.6%) had CML-CP, 21 (7.4%) pts had CML-AP and 79 (27.9%) pts had de-novo CML-BP. For the 204 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 22.5 months (1-207 months). Median age at diagnosis of CML-BP was 50 years (range 16-86 years). EM disease was present in 78 (27.6%) pts (38 myeloid sarcoma, 30 central nervous system and 10 skin). Blasts were of myeloid phenotype in 168 (59.4%), lymphoid in 103 (36.4%) and mixed in 9 (3.2%) pts. The bcr-abl protein was p210 in 229 (80.9%), p190 in 8 (2.8%) and p230 in 2 (0.7%) pts. ABL kinase domain mutation was seen in 42.1% (80/190) pts, with T315I being the most common (n=32), followed by E255K (n=16). Next generation sequencing was performed in 117 pts. The most common mutations were ASXL1 (n=27), RUNX1 (n=14), BCOR (n=4), DNMT3A (n=4) and BCORL1 (n=3). Of the 283 pts, 269 underwent CML-BP directed therapy. 63 (23.4%) pts were treated with TKI monotherapy, 184 (68.4%) pts were treated with a combination of chemotherapy (chemo) and TKI and 22 (8.2%) pts were treated with chemo alone. Response rate after CML-BP directed therapy was 75.3% (n=213). Best response was return to CML-CP in 49 pts, CHR with PCyR in 18 pts, CCyR in 31 pts, MMR in 31 pts, MR4 in 18 pts, MR4.5 in 19 pts and MR5 in 47 pts. Rate of response with 2G and ponatinib was significantly better than imatinib (85.3% and 77.3% vs 63.6%; p=0.04). 149 (55.4%) pts proceeded to alloSCT. Of the 213 pts that responded, 59 (27.7%) relapsed. At a median follow-up of 47 months, the median OS for all pts was 19.7 months (95% CI: 16.3-40.2 months), with 5-year OS rate of 38% (95% CI: 32-45%). Pts with myeloid phenotype had a significantly lower OS compared to lymphoid and mixed phenotype (Median OS 14.9 vs 45.9 and 31.1 months respectively; p=0.02). OS of pts that were treated with a combination of TKI and chemo was significantly longer compared to pts treated with TKI or chemo alone (52.9 vs 16.1 or 7.5 months; p&lt;0.0001). Dasatinib (n=99; 34.9%) and ponatinib (n=97; 34.3%) were the most used TKIs followed by imatinib (n=23; 8.1%), nilotinib (n=21; 7.4%), bosutinib (n=8; 2.8%) and asciminib (n=3; 1.1%). Pts treated with ponatinib had a numerically longer OS compared to 2G-TKI and imatinib, however this was not statistically significant (40.1 vs 30.6 and 20.3 months; p=0.52). EFS for pts treated with ponatinib was significantly longer compared to 2G-TKI or imatinib (25.9 vs 17.6 and 15.9 months; p=0.03). In a landmark analysis, pts that underwent alloSCT within 6 months of diagnosis had a significantly longer OS compared to those who did not (69.3 vs 16.0 months; p=0.006). Conclusion: CML-BP continues to have poor prognosis. Treatment is heterogenous involving various combinations of TKI and chemo. In our analysis, treatment with 2G-TKI or ponatinib led to better responses. CML-BP with myeloid phenotype had worse OS. Treatment with ponatinib was associated with a numerically longer OS and significantly longer EFS compared to 2G-TKI and imatinib. In addition, treatment with chemo in combination with TKI and alloSCT led to improved OS.

Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

Abstract Background: IEC-HS is a potentially life-threatening complication following CAR-T therapy in RRMM. Reliable diagnostic biomarkers are needed to help expeditiously identify cases to initiate prompt treatment and supportive care. Serum ferritin, a routinely available laboratory parameter, is commonly elevated in IEC-HS and has been used to identify cases. However, ferritin can also be elevated in cytokine release syndrome (CRS) or secondary to baseline tumor-related inflammation. The optimal diagnostic threshold for post-CAR-T ferritin in IEC-HS in RRMM has not been previously established. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium to identify the optimal post-CAR-T ferritin threshold to distinguish RRMM patients (pts) with and without a diagnosis of IEC-HS. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold based on Youden's Index. The performance of the threshold was evaluated overall and stratified by CAR-T product (cilta-cel, ide-cel). Additional analyses included the temporal relationship of peak ferritin and IEC-HS diagnosis, the evaluation of IEC-HS criteria according to ferritin levels, comparison of IEC-HS criteria co-occurrence, and comprehensive baseline characteristic comparisons across ferritin strata. Results: Of 1502 RRMM CAR-T recipients (ide-cel, n=712; cilta-cel, n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. A post-CAR-T ferritin threshold of 7470 ng/mL was identified as optimal for distinguishing pts with and without IEC-HS (AUC 0.938). Sensitivity (0.904) and specificity (0.934) were both very high, indicating high discriminatory ability. Stratified ROC analyses showed near-identical optimal thresholds for cilta-cel (7450 ng/mL; sensitivity 0.885, specificity 0.936, AUC 0.94) and ide-cel (7470 ng/mL; sensitivity 0.952, specificity 0.933, AUC 0.95), indicating minimal impact of CAR-T product on ferritin's prognostic utility. Baseline pt characteristics (N=1,413) differed significantly by ferritin threshold. Pts above the ferritin threshold of 7470 (N=154) were younger (median 64 vs 67 years; p=0.004), more frequently male (65% vs 56%; p=0.043), had higher baseline ferritin (1,300 vs 187; p&lt;0.001), higher ECOG at apheresis (p=0.001), more likely penta-refractory (p=0.016), had higher baseline bone marrow plasma cell burden (p&lt;0.001), and had higher R-ISS scores (p&lt;0.001). Evaluation of IEC-HS criteria (Hines et al, TCT 2023) demonstrated significantly higher rates of laboratory and clinical criteria, including hepatic transaminase elevation (43% vs 15%), hypofibrinogenemia (53% vs 0%), cytopenias (95% vs 81%), hypertriglyceridemia (43% vs 8%), ICANS (52% vs 23%), renal insufficiency (20% vs 0%), and soluble IL-2 receptor elevations (47% vs 4%), in pts with ferritin &gt;7500 ng/mL compared to those with lower ferritin. Heatmap visualization revealed distinct patterns of co-occurring criteria in high- and low-ferritin groups. Assessment of the timing of peak ferritin and IEC-HS diagnosis among IEC-HS cases revealed a median difference of 0 days (IQR: -1, 0), suggesting simultaneous occurrence. Median time to max ferritin was 9 days (IQR 8,12) in IEC-HS pts compared to 8 days (IQR 5,10) in non-IEC-HS pts (Wilcoxon p&lt;0.05). Conclusions: In this analysis of over 1500 patients, a post-CAR-T ferritin level of 7500 ng/mL robustly identifies RRMM pts with IEC-HS following either cilta-cel or ide-cel. Pts exceeding this threshold demonstrate marked enrichment in IEC-HS diagnostic criteria and significant differences in baseline characteristics, warranting further study of the role of ferritin in IEC-HS diagnosis and early intervention.

Abstract Introduction: IEC-HS is an emerging and potentially life-threatening complication in multiple myeloma (MM) patients (pts) treated with CAR-T therapies. We conducted a retrospective, multi-institutional analysis to define the features and outcomes of IEC-HS after ide-cel or cilta-cel in the real-world setting. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium for patients with relapsed/refractory MM (RRMM) who received commercial cilta-cel or ide-cel. IEC-HS was defined by each center based on diagnostic criteria (Hines et al, TCT 2023). Kaplan-Meier and multivariable Cox models were used for time-to-event outcomes while logistic regression was used for categorical outcomes. Results: Of 1502 RRMM pts who received either ide-cel (n=712) or cilta-cel (n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. Product-specific incidences were 2.9% for ide-cel and 6.7% for cilta-cel. The median time from CAR-T infusion to IEC-HS onset was 9.5 days (range 2-37 days). IEC-HS-related clinical findings (Hines et al, 2024) included cytopenias (95%), elevated soluble IL-2R levels (79%), fever (76%), elevated LDH (71%, median 1,800 U/L), hypofibrinogenemia (70%), hypertriglyceridemia (65%), ICANS (63%), hepatic transaminase elevation (56%), pulmonary involvement (46%), renal insufficiency (29%), hyperbilirubinemia (22%), and hemophagocytosis in bone marrow (6%). The median interval from peak CRS to IEC-HS onset was 4 days (IQR 1–6). Some variables, such as splenomegaly and coagulopathy, were not systematically collected. Nearly all pts received pharmacologic intervention: corticosteroids (94%, n=59), anakinra (76%, n=48), tocilizumab (71%, n=45), emapalumab (13%, n=8), ruxolitinib (16%, n=10), or etoposide (3%, n=2). Only one pt (2%) did not receive any IEC-HS therapy. Among those evaluable for outcomes, 58% (n=35) improved, 12% (n=7) developed further CAR-T-related complications (e.g., recurrent IEC-HS, delayed neurotoxicity), and 30% (n=18) had no therapeutic response and died. Compared to non-IEC-HS pts (n=1,428), those with IEC-HS were younger (median age 63 vs 66), male (61% vs 57%), and more frequently received cilta-cel (72% vs 52%, all p&lt;0.01). They had higher rates of triple-class (81%) and penta-refractory (43%) disease, greater pre-treatment bone marrow plasma cell burden (40% vs 6%), and higher baseline ferritin (1058 vs 208 ng/mL). Prior autologous SCT was less common, and advanced R-ISS stage was more prevalent. IEC-HS was associated with dramatically worse PFS and OS: with cilta-cel, median PFS was 6.5 months (mo) with IEC-HS (vs 33.1 without); for ide-cel, 8.9 vs 11.4 mo. Median OS for cilta-cel IEC-HS pts was 9.6 mo (not reached in non-IEC-HS pts); for ide-cel IEC-HS, 19.6 mo (vs 40.8 mo). Multivariable analysis confirmed IEC-HS as an independent predictor of shorter PFS (HR 1.88, 95% CI 1.29–2.74, p=0.0011) and OS (HR 2.30, 95% CI 1.39–3.83, p=0.0013). Notably, IEC-HS was not associated with lower response rates – either best CR (63.9% vs 64.0%, p=0.71) or ORR (91.8% vs 90.9%, p=0.97). Cilta-cel pts had a higher probability of achieving a deep (CR) response, regardless of IEC-HS status. Grade &gt; 3 CRS occurred in 14% (n=3/21) of ide-cel and 15% (n=8/52) of cilta-cel IEC-HS pts, versus 2% (n=12/691) and 2% (n=13/737) in non-IEC-HS pts, respectively. Any-grade ICANS was observed in 67% (n=14/21) of ide-cel and 55% (n=29/52) of cilta-cel IEC-HS cases, compared to 26% (n=179/690) and 20% (n=148/738) in non-IEC-HS. Grade ≥3 ICANS occurred in 29% (n=6/21) of ide-cel and 26% (n=14/52) of cilta-cel IEC-HS cases, relative to 4% (n=25/690) and 4% (n=27/738) in pts without IEC-HS. Severe infections were also more common: 71% (n=15/21) of ide-cel and 53% (n=28/52) of cilta-cel IEC-HS pts experienced at least one infection, compared to 31% (n=214/691) and 29% (n=217/737) in non-IEC-HS groups. Conclusions: IEC-HS is an uncommon but severe and early complication after CAR T-cell therapy for RRMM. Despite similar ORRs with or without IEC-HS, IEC-HS was associated with significantly worse PFS and OS for both ide-cel and cilta-cel. These findings support the need for vigilant monitoring and potential preemptive treatment strategies to better manage this syndrome.