Citations

Background and Methods: IEC-HS is a hyperinflammatory state with high morbidity and mortality. Effective interventions to reverse the process early in the clinical course may be critical to improve outcomes. We previously examined cytokine differences between IEC-HS and other secondary hemophagocytic lymphohistiocytosis, and found significant differences in the patterns and outcomes.(1) This study examines cytokine profiles (CP) of patients treated with CAR-T from 9/2019 to 3/2024 who developed CRS, MAS-L and IEC-HS. Demographics and lab results were compared among the three groups and correlated with outcomes. Results: CP was tested in 113 of 366 CAR-T patients: 74 with CRS, 19 with MAS-L, and 20 with IEC-HS. The racial distribution was 93% White/Caucasian, 2% Black or African American, 1% Asian, 1% Native American and 3% other or unavailable. No differences were seen in demographics between groups except a higher percentage of patients with ECOG performance status ≥2 in IEC-HS (p=0.037). Incidence of IEC-HS by disease: 3.6% (7/193) in lymphoma, 5% (8/159) myeloma and 28.5% (4/14) B-acute lymphoblastic leukemia (p=0.0002). Incidence of IEC-HS by CAR-T product: 3% (4/150) in Axi-cel, 23% (6/26) in Brexu-cel, 8% (1/13) in Tisa-cel, 5% each (3/60) in Cilta-cel and Ide-cel, and 0/17 in Liso-cel (p=0.001). Prior to lymphodepletion, labs were already different among the CRS, MAS-L, and IEC-HS groups: hemoglobin (g/dL: 11.1, 9.6, 8.45); platelets (x109/L: 168, 116, 52.5); ferritin (µg/L: 115, 946, 1944). CP was started when patients needed a second dose of tocilizumab or concern for developing MAS-L/IEC-HS, and continued daily until clinical improvement or resolution of inflammatory state. Tocilizumab and dexamethasone use were similar across groups. Other therapies used were vasopressors (3%, 10.5%, 45%; p<0.0001), Methylprednisolone (20%, 31.6%, 50%; p=0.027), Anakinra (12%, 63%, 85%; p<0.0001), Siltuximab (9.5%, 16%, 30%; p=0.06), Basiliximab (30% of IEC-HS), and continuous veno-venous hemofiltration (30% of IEC-HS). Among the first CP, the CRS group had lower levels of cytokines (in pg/mL) compared to MAS-L and IEC-HS groups: TNF (31, 62.9, 47.7), IL-10 (29.3, 97.7, 169), IL-18 (794, 1353, 2011), IFN-gamma (74, 281, 250), MCP-1 (689, 2722, 2485.5), MIP-1 alpha (220, 234, 247.5), IL-6 (>315: 45%, 79%, 70%), soluble IL-2R alpha (>4000: 45%, 84%, 70%). The percentage of patients who received anakinra before CP1 were 4% (CRS), 21% (MAS-L) and 25% (IEC-HS) (p=0.007). IL-1 beta was below threshold among all patients who received anakinra in CRS and MAS-L and 75% in IEC-HS, suggesting rapid and effective IL-1 suppression by anakinra except in IEC-HS. Cytokines trends 24 hours and 48 hours after the first CP differed between MAS-L and IEC-HS. MAS-L had decreased TNF (62.9, 40.4, 18.5) and MCP-1 (2722, 355, 104) while these cytokines remained elevated or increased in IEC-HS (TNF: 47.7, 105.5, 62.6; MCP-1: 2486, 2276, 1585). IL-18 was minimally elevated in MAS-L (1353, 1955, 3068) and significantly increased in IEC-HS (2011, 2420, 4048). Notably, CP2 and CP3 levels of these cytokines in IEC-HS were statistically significantly higher than corresponding CPs among CRS and MAS-L. In addition, patients who died with persistent E. faecium bacteremia had higher IL-18 on CP3. Infections occurred in 43%, 58%, and 85% respectively (p=0.002), including E. faecium bacteremia (3%, 5%, 35%; p=0.0004), CMV viremia (30% of IEC-HS patients vs. 11% of non-IEC-HS; p=0.025), and invasive fungal infections (15% of IEC-HS patients; p=0.0001). Between the IEC-HS and non-IEC-HS groups, day 100 non-relapse mortality was 35% vs. 0 (p<0.0001), day 100 all-cause mortality was 45% vs. 3% (p<0.0001), and E. faecium bacteremia-related deaths were 50% vs. 1% (p<0.0001). Conclusions: CRS, MAS-L andIEC-HS are known complications of CAR-T. Cytokine-directed therapy can modify the cytokine milieu and control the inflammatory process. However, excess immunosuppression may result in life-threatening infections. Further studies are needed to identify optimal biomarker-guided immunosuppressive strategies to control the inflammatory cascade, while avoiding excess immunosuppression. References: 1. Leung, Nelson, et al. “Outcomes of patients who received CAR T cell therapy and developed IEC-HS treated with cytokine directed therapy.” (2024): 7516-7516.

Background: Recent advancements in multiple myeloma (MM) diagnosis and treatment significantly improved patients' survival and quality of life. Severe Renal Impairment (RI) remains a significant challenge in newly diagnosed MM (NDMM), complicating treatment and affecting outcomes. Prior studies reported improved overall renal recovery in the era of novel therapies. However, there is a lack of evidence documenting the outcomes of patients presenting with severe RI. We present an updated analysis of the characteristics and outcomes of patients with NDMM presenting with severe RI in an ethnically diverse, low socio-economic population. Methods: A single-center retrospective review of patients with NDMM presenting to Montefiore Medical Center (Bronx, New York) was conducted from 2011-2023. Severe RI was defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m². MM risk was assessed using the mSMART 3.0 tool. Results: Out of 284 patients with NDMM, 58 (20%) patients presented with severe RI. Black patients (p = 0.018) and older adults (64 years vs 60 years, p value 0.032) were more likely to present with severe RI. Severe RI at diagnosis correlated with high-risk myeloma (p = 0.002), high R-ISS stage (p < 0.001), and a lower likelihood of receiving stem cell transplants (p < 0.001). Among those with severe RI, 23/58 required dialysis of which 6/23 were taken off dialysis at last follow-up after renal recovery. Median eGFR at diagnosis, 6 months and 1 year after diagnosis was 11, 23 and 23.5 ml/min/1.73 m2, respectively. 14 out of 58 patients (39%) achieved renal recovery to eGFR > 30 one year post-diagnosis, with no significant difference in race, sex, or ethnicity. The most common first-line treatment for patients with severe RI was CyBorD (62%). The median time from diagnosis to first treatment (including plasma exchange) was 10 days. By the last follow-up, 35/58 patients (60%) had a stem cell transplant, with a median time from diagnosis to transplant of 275 days. The median overall survival (OS) for patients with severe RI at diagnosis was 49 months, while it was not reached for those without severe RI (p < 0.001). Early death (≤ 2 months after diagnosis) occurred in 2 patients, both with severe RI. Among patients with severe RI, multivariate Cox regression survival analysis showed that achieving free light chain (FLC) below 500 mg/L (HR 0.212, p < 0.001) and receiving a stem cell transplant (HR 0.209, p 0.002) improved outcome. Conclusions: Despite improvements in the life expectancy of patients with MM, severe renal failure remains a challenge, particularly among minorities. Socioeconomic factors need to be explored as a contributor to outcomes in patients with severe RI. Achieving FLC clearance and undergoing stem cell transplant may play a role in survival in patients with NDMM and severe RI.

Background: Despite effective front-line therapies, DLBCL & MM have high relapse rates. Novel therapies like CAR-T & bispecific antibodies (BsAb) offer deep & durable remission compared to salvage therapies, but have a unique toxicity profile (TP) that requires monitoring. With no head-to-head trials, the rationale for therapy selection may vary. This study explores provider choices, sequencing preferences, & access barriers. Methods: Two anonymous surveys (MM and DLBCL) of US-based Hematologists were conducted from 2/2024 to 6/2024, on practice settings, CAR-T & BsAb availability, treatment preferences & barriers. Responses were analyzed to assess preferences across clinical scenarios. Results: Surveys were completed by 37 MM & 45 DLBCL providers. Most were at centers offering both CAR-T & BsAb. Most gave CAR-T inpatient, & BsAb outpatient. CAR-T was given by 73% MM providers & 66% DLBCL (92% used Cilta-cel, 96% used Ide-cel; 100% used Axi-cel, 90% used Liso-cel & 73% Tisa-cel). In MM, 78% used Teclistamab, 60% Talquetamab & 24% Elranatamab. In DLBCL, 62% used Epcoritamab & 40% Glofitamab. Providers preferred CAR-T over BsAb in MM after 4+ prior lines of therapy (LOT) (89%), & in DLBCL after 2+ prior LOT (93%). CAR-T was favored more among academic providers & those at CAR-T centers. Practice volume did not impact selection. Among providers at centers with BsAb-only, CAR-T was preferred by 60% (MM) and 50% (DLBCL). Providers at centers without both favored CAR-T (MM: 75%, DLBCL: 86%). CAR-T was chosen for better outcomes, short treatment, center choice, & prior experience. Other factors that influenced decisions were lower incidence of cytopenia/infection & “BsAb effective post-CAR-T, less so vice versa” (MM), & “curative potential of CAR-T” (DLBCL). Logistical barriers & institutional constraints influenced BsAb selection: CAR-T unavailability, access to specialized centers, referral complexity, insurance delay, manufacturing delay & hospitalization needs. In MM, 78% providers preferred Cilta-cel over Ide-cel, especially academic providers & those with CAR-T experience. CAR-T volume did not impact selection. Cilta-cel was preferred due to perceived better response rate (RR), more experience, “progression-free survival (PFS) benefit”, center choice, & logistical issues with Ide-cel. Ide-cel was selected due to center choice, favorable TP & insurance preference. Teclistamab was preferred by 78% due to more experience, better RR, TP & center choice, Elranatamab by 11% (better TP, RR, & “PFS”), & Talquetamab by 11% due to having a non-BCMA target. Academic providers preferred Teclistamab (89% vs 50%), & nonacademic providers preferred Talquetamab (38% vs 4%) and Elranatamab (13% vs 8%). In DLBCL after 2+ LOT, 69% favored Axi-cel due to prior experience, RR, center choice, & logistical issues with other products. Liso-cel & Tisa-cel were chosen by 27% & 2%, respectively, due to favorable TP. Axi-cel was also preferred 2nd line by 73% for similar reasons, while 24% favored Liso-cel for its favorable TP. Epcoritamab was preferred by 56% (subcutaneous injection, more experience & center choice) & Glofitamab by 42% (shorter treatment duration, easy administration, more experience, & center choice). Practice setting & volume did not impact selection between products in DLBCL. InBCMA-naïve MM pts, majority (97%) chose an anti-BCMA agent over GPRC5D due to better RR, TP, prior experience, & center choice. InBCMA-exposed pts, most (92%) favored an anti-GPRC5D agent. In contrast in DLBCL, 80% chose CD19 CAR-T after prior CD19-directed therapy, & 18% chose CD20 BsAb. Therefore, antigen escape was less of a concern in DLBCL vs MM. For relapse after 2nd line CAR-T in DLBCL, 78% preferred BsAb over other salvage options due to better RR, TP, & more experience. Providers prioritized RR, survival, & TP in decision making. Treatment logistics, duration, frequency, & cost were less crucial. MM providers also prioritized quality of life, which was less so in DLBCL. There were no differences in priority based on practice setting & experience with CAR-T. Conclusion: The study highlights factors influencing therapy choices in MM & DLBCL. Despite CAR-T's potential for better outcomes, significant access barriers exist. Efforts to streamline referral pathways, logistics, & expanding availability are crucial to improve outcomes. Understanding these preferences & barriers can guide future management strategies.

Diagnosis of motor neuron diseases and other corticospinal tractopathies requires a comprehensive approach that integrates clinical symptoms and laboratory findings with findings from conventional MRI and advanced neuroimaging.

Abstract Purpose: Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined. Experimental Design: Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. Results: We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton’s tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells. Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL.

Introduction: Living in an area with high Area Deprivation Index (ADI) is linked to worse cardiovascular disease (CVD) outcomes. However, the association of ADI with type 2 diabetes (T2D), a major CVD risk factor, is incompletely described. This knowledge may guide primary CVD prevention. Method: Rochester Epidemiology Project is a medical record linkage system of persons in southeast Minnesota and southwest Wisconsin. We identified 253,890 persons (aged 4–98 yrs on July 1, 2015) in 9 counties with >90% population coverage. ADI scores, from 2015 home addresses, were grouped into quartiles of low (Q1) to high (Q4) deprivation. We excluded persons with type 1 diabetes (T1D) or history of T2D and identified new T2D cases (2015-2020) using ICD codes, HbA1c and medications. We examined the association between ADI quartile and risk of incident T2D using Cox regression with persons right censored at death, T2D, T1D or last visit. Models were adjusted for age and gender, and reported adjusted hazard ratios (aHR [95% confidence interval]). Results: Age, gender, and race statistically differed across ADI quartiles (Table). Age × ADI interaction was significant ( P <.001). T2D incidence ranged from 6.3 (Q1) to 9.0 (Q4) per 1000 person-years ( P <.001). Women vs. men/non-binary persons (combined due to limited non-binary persons) had 30% lower risk of incident T2D (aHR 0.70 [0.67–0.72]). Risk of incident T2D was higher in persons from higher ADI areas. At median age of 48.6 yrs, the risk was 30% higher in Q2 (aHR 1.3 [1.22–1.38]), 38% higher in Q3 (aHR 1.38 [1.30–1.47]) and 53% higher in Q4 (aHR 1.53 [1.43–1.62]) vs. Q1. Higher ADI was associated with higher incident T2D in younger persons, with risk attenuation with increasing age (Figure). Conclusion: In this population cohort, persons, particularly of younger age, living in more deprived areas had a higher risk of incident T2D. ADI may help identify areas for targeted T2D screening, with implications for CVD screening and prevention.

Background: Risk stratification for embolism in cardiac myxomas remains poorly explored. Goals: By this meta-analysis we studied the risk factors assicated with embolism among patients with cardiac myxoma. Methods: A comprehensive search was conducted across PubMed, Embase, Cochrane Library, and Google Scholar from their inception until January 2024. Statistical analyses were performed using Cochrane's RevMan 5.4 software. For each risk factor, the pooled odds ratio or mean difference was calculated along with the corresponding 95% confidence interval. Results: We included 18 studies in our analysis with a total population of 2601 out of which 525 patients (20.1%) had at least one episode of embolism. The pooled analyses showed that hypertension (p = 0.001), New York Heart Association I/II (p = 0.03), irregular tumor surface (p <0.00001), hyperlipidemia (p < 0.0001), coronary artery disease (p=0.01), high mean platelet volume (p=0.02), high tumor mobility (p<0.00001), were significantly associated with increased incidence of embolism. Female gender (p = 0.03) was the only risk factor associated with reduced risk. Other factors like smoking, atrial fibrillation, tumor size, age, body mass index (BMI), diabetes, left ventricular ejection fraction (LVEF), left atrial diameter (LAD) were not significantly associated with embolism (p > 0.05). Conclusion: Our study is the first to report significant pooled outcomes for gender, hyperlipidemia, coronary artery disease, mean platelet volume, and tumor mobility in the population discussed. Hypertension, New York Heart Association I/II, irregular tumor surface, hyperlipidemia, coronary artery disease, mean platelet volume and tumor mobility were significantly associated with high risk while female gender was associated with low risk of embolism. Patients with high-risk factors might benefit from early evaluation and definitive treatment (surgery).

Abstract Effective immune synapses are a prerequisite for desirable immune surveillance and control of tumour growth. Cell-to-cell interactions form the basis of immune synapses, resulting in either immunoprotected or immunosuppressed manifestations in the tumour brain that could explain glioblastoma (GBM) recurrence. Using state-of-the-art multiplex imaging, spatial statistics, and spatially aware deep learning tools in 14 patient-matching tissues from primary and recurrent GBM, we detected spatial immune networks (SINets). SINets across 105 regions of interest comprising 2.3 million cells show stronger spatial engagement between myeloid and lymphoid lineages at recurrence. SINets’ architecture in primary tumours is associated with relapse timing. Patients, where the SINets are more modular, recur sooner than patients with denser SiNets. In addition, this association presents sexual dimorphism in our cohort (N=3 females, and N=4 males). Phenotype-to-phenotype spatial coexistence also contributes to enhancing phenotype prediction. A spatial-aware deep learning model trained with single-cell data from primary tumours reaches an average balanced accuracy of 0.76 in primary tumour cellular communities unseen during training, compared to a spatial-agnostic model that reached an average balanced accuracy of 0.69. In summary, we detected a distinct spatial engagement in glioblastoma undergoing chemo-radiation treatment. The spatial patterns of coexistence represent ecological niches that contribute to defining cell occurrence and may underpin effective immune synapses. Overall, the spatiotemporal elements provide a newer approach for dissecting glioblastoma’s complexity and discovering opportunities for stratifying patients by harnessing spatial information encoded in multicellular niches.

Abstract Despite exhibiting longer overall survival that IDH-wt counterparts, IDH-mutant gliomas remain uniformly deadly and impact patients in the prime of adult life. The immune microenvironment of IDH-mutant gliomas remains incompletely characterized, particularly with regard to distinctions between IDH-mutant astrocytoma and IDH-mutant, 1p/19q codeleted oligodendroglioma. To address this knowledge gap, we subjected dissociated tumor suspensions derived from 7 astrocytoma and 7 oligodendroglioma clinical samples to flow cytometry-based sorting for the pan-immune marker, CD45, and the microglial marker, P2RY12. This process yielded both microglial and non-microglial immune cell populations, which were then analyzed by scRNA sequencing. This workflow revealed a single large cluster of microglia, characterized by expression of Galectin-1 and lysosomal Lipase A, which was present at a significantly higher level in oligodendroglioma. While the biological significance of this cluster is unclear, gene set enrichment analysis exploring phenotypic differences between microglia in astrocytoma and oligodendroglioma revealed significant increases in expression of gene sets related to antigen presentation in astrocytoma. Parallel analysis of the non-microglial immune fraction showed an increase in the expression of pro-inflammatory gene sets, such as genes related to cytokine secretion, within the CD8 T-cell compartment of astrocytomas. We also observed upregulation of the expression of inflammatory gene sets within the dendritic cells of astrocytomas. Taken together, these changes suggest that the immune compartment of astrocytoma is more active and inflamed, and targeting the immune system in these tumors may represent a potential therapeutic avenue.