Citations

Background Cardiovascular disease (CVD) is a leading cause of death in cancer survivors. Predicting CVD risk in this population remains challenging. Risk prediction models that use machine learning algorithms could provide an objective method for accurate risk prediction to facilitate the prevention and management of CVD in cancer survivors. We evaluated previously tested machine learning algorithms and logistic regression (regularized by machine learning methods), in addition to testing and validating newer, more complex machine learning algorithms, for CVD prediction in cancer survivors. Methods This multicenter study used a database of 3835 multiracial cancer survivors with 89 clinical, laboratory, and echocardiographic features over 20 years. Models were trained using repeated random and time‐split samples and tested on a separate cohort of 329 patients. Model performance was assessed using the area under the receiver operating characteristic curve. Results Regularized logistic regression achieved an area under the receiver operating characteristic curve of 0.845 (heart failure), 0.783 (atrial fibrillation), 0.792 (coronary artery disease), and 0.806 (composite CVD). These are comparable to 0.837 and 0.848 for heart failure, using Bayesian additive regression tree and random forest as more advanced machine learning models, respectively. De novo composite CVD (post‐cancer diagnosis) was also predicted with an area under the receiver operating characteristic curve of 0.826 using regularized logistic regression, compared with 0.735 and 0.802 using decision tree and random forest, respectively. Conclusions Regularized logistic regression and advanced machine learning models demonstrated similar predictive performance, with institutional transferability. These tools may support risk stratification and prevention strategies in cardio‐oncology using longitudinal data. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05377320.

Background: Accurate characterization of tumor stiffness and adhesion is crucial when surgically resecting meningiomas. Currently, such determinations are difficult to ascertain through standard preoperative imaging diagnostics and clinical experience. Herein, we explored magnetic resonance elastography (MRE) as a means of assessing these parameters and thereby improving neurosurgical resections. Methods: This prospective study of 193 patients with meningiomas involved three distinct patient subsets (cohort 1, 88 [2017–2021]; cohort 2, 55 [2022–2023]; cohort 3, 50 [2023–2024]. We analyzed preoperatively obtained MRE data on meningioma stiffness (cohorts 1 and 2) and adhesion (cohort 2) for accuracy, while matching subjects with or without MRE studies (cohort 3, 1:1 ratio) to define the role of preoperative MRE in improving operative outcomes. Results: Areas under the curve (AUCs) for MRE in gauging meningioma stiffness and adhesion were 0.87 and 0.89, respectively. Both parameters significantly surpassed empiric predictions of stiffness and adhesion rendered by surgeons and radiologists, based on routine magnetic resonance imaging (MRI). MRE-determined stiffness measures independently correlated with prolonged resection duration, whereas MRE-assessed adhesion showed independent associations with increased blood loss, longer duration of tumor resection, and higher risk of pial injury. Ultimately, results based on cohort 3 demonstrated that MRE has great potential in this setting to improve neurosurgical procedures by significantly reducing intraoperative bleeding, resection duration, and risks of pial injury. Conclusion: MRE is a promising, noninvasive tool for accurately assessing meningioma stiffness and adhesion, standing to improve the precision and safety of needed surgical intervention.

Introduction: This study investigated the association between capitate morphology and the success rates of non-vascularized bone graft (NVBG) and vascularized bone graft (VBG) operations for scaphoid nonunion. Methods: We retrospectively analysed 213 patients with established scaphoid non-union who underwent either non-vascularized bone graft ( n = 75) or vascularized bone graft ( n = 138). We analysed risk factors, including demographics, medical history, implant type, previous surgery, bone graft donor site and capitate morphology for their association with treatment outcome. We also assessed the relationship between capitate and scaphoid morphology in the uninjured wrists of 31 patients. Results: The overall success rate was 81% for NVBG and 86% for VBG, with no significant difference. For NVBG, Type II capitate, age 40 or older and tobacco use were significant risk factors for failure. For VBG, only previous surgery was a significant risk factor. In uninjured wrists, a Type II capitate was associated with a significantly thinner scaphoid waist and a lower waist index than a Type I capitate. Conclusion: Our study introduces a new radiographic classification of capitate morphology and establishes its significant association with scaphoid morphology. Beyond traditional factors, capitate morphology can help to assess scaphoid morphology and potentially infer vascularity, aiding the selection of the most appropriate bone graft type for treating scaphoid non-union. Level of evidence: III

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Background Despite CD19-directed chimeric antigen receptor T (CAR-T) therapy achieving remarkable remission rates in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), long-term survival remains constrained by T-cell exhaustion and immunosuppressive microenvironments. Dasatinib, a tyrosine kinase inhibitor (TKI), has been shown to alleviate T cell exhaustion and enhance CAR-T cell persistence, demonstrating therapeutic synergy in newly diagnosed ALL. However, it may also suppress CAR-T cytotoxicity and is ineffective against BCR-ABLT315I mutations. Third-generation TKIs, including ponatinib and olverembatinib, effectively overcome T315I-mediated resistance, yet their impact on CAR-T cell function and immune modulation remains insufficiently defined. Methods and Results: We first established in vitro co-culture models of CD19 CAR-T cells with the B-ALL cell line NALM6 to evaluate the effects of dasatinib, ponatinib and olverembatinib on resting and tumor antigen-activated CAR-T cells. At clinically relevant concentrations, none of the TKIs affected resting CAR-T viability. In contrast, upon activation, all three TKIs significantly inhibited CAR-T activation, cytotoxicity, and cytokine secretion (IL-2, TNF-α, IFN-γ), while reducing activation-induced CAR-T cell apoptosis. TKIs treatment also downregulated exhaustion markers (eg. PD-1, TIM3, LAG3) and promoted differentiation toward naïve (TN) and central memory (TCM) subsets, while reducing terminal effector T cells. After the drug elution, CAR-T cells regained their cytolytic function in response to tumor targets. Notably, ponatinib-treated CAR-T cells exhibited higher levels of IFN-γ, TNF-α and IL-2 post-washout compared to other groups. Importantly, the TN/TCM phenotype and low exhaustion marker expression were preserved after washout in all TKI-treated groups. Transcriptomic profiling of CAR-T cells in vitro revealed that all three TKIs downregulated key exhaustion-associated genes, including PDCD1, HAVCR2, CTLA4 and NR4A1, along with upregulation of stemness- and memory-associated genes (eg. CCR7, TCF7, LEF1, IL7R). Gene set enrichment analysis showed inhibition of T-cell activation, apoptosis, glycolysis, and TGF-β signaling by all TKIs. Remarkably, ponatinib uniquely activated the IFN-γ pathway, suggesting superior immunostimulatory effects. Mechanistically, all three TKIs suppressed the phosphorylation of AKT, p38 MAPK, and NF-κB p65, indicating shared inhibition of downstream TCR signaling. Based on these findings, we evaluated ponatinib in a clinical setting. A prospective study (No. ChiCTR2000036350) enrolled three R/R B-ALL patients with the BCR-ABLT315I mutation. All the patients received CD19 CAR-T cell therapy followed by ponatinib maintenance, initiated two months post-infusion. All three patients remained progression-free during ponatinib maintenance. Notably, the DNA copies of CAR-T cells remained detectable at months 5 and 9 after ponatinib treatment in two patients, respectively. To further explore the in vivo effects of ponatinib on T cells and other immune cells,peripheral blood mononuclear cells were collected from these patients before and one month after ponatinib initiation for single-cell RNA sequencing. Ponatinib exposure led to an increased proportion of CD8+T cells and a decreased abundance of myeloid cells subsets. Within T cells, effector cells expanded while Tregs and exhausted T cells decreased. Differential gene analysis showed suppression of activation, adhesion, apoptosis, and PD-1/PD-L1 signaling, aligning with in vitro results. Functional scoring revealed enhanced cytotoxicity, IFN-γ responses, and reduced glycolysis, exhaustion, TGF-β, and Treg signatures. Furthermore, analysis of NK cell subsets showed enhanced cytolytic scores and enrichment of proliferation and immune activation pathways, suggesting that ponatinib preserves innate immune responses in vivo. Conclusions: This study provides preclinical and preliminary clinical evidence that third-generation TKIs, particularly ponatinib, can effectively alleviate CAR-T cell exhaustion, promote memory phenotypes, and remodel the immune microenvironment. Compared to dasatinib and olverembatinib, ponatinib uniquely enhances effector cytokine production and activates the IFN-γ pathway. These findings support ponatinib as a promising combinatorial agent with CAR-T therapy, offering a rational strategy for improving outcomes in patients with T315I-mutated R/R B-ALL.

Abstract Preiser's disease (PD), or idiopathic avascular necrosis of the scaphoid, is a debilitating condition leading to wrist pain, dysfunction, and pan-carpal arthritis. While impaired scaphoid vascularity is central to its pathogenesis, identifying individuals at risk is challenging due to the morphological distortion of the scaphoid as the disease progresses. This study aims to investigate the association between a novel capitate morphology classification, scaphoid morphology, and their impact on PD prevalence and characteristics. We also re-evaluate negative ulnar variance (NUV) as a potential risk factor for PD. This retrospective case–control study included 34 PD patients and 340 age-matched controls. Capitate morphology was classified into Type I/II on anteroposterior (AP) radiographs based on capitotrapezoid–scaphocapitate (CT–SC) joint line angle and ratio. Scaphoid morphology was assessed via the waist index on contralateral healthy wrists. Radiographic measurements of ulnar variance and PD staging were also performed. Statistical analyses compared morphological prevalence and risk factors between groups. Type II capitate was significantly more prevalent in the PD group (35.3%) than in controls (17.1%, p = 0.018). Similarly, NUV was significantly higher in PD patients (29%) compared with controls (6.8%, p < 0.001). We found a strong correlation between Type II capitate and slender (Type II) scaphoid morphology in healthy wrists. No significant differences in age, gender, or affected side were observed. Interobserver and intraobserver agreements for capitate classification were substantial (kappa ≥0.882). Our study introduces a reliable radiographic method for classifying capitate morphology, which strongly correlates with intrinsic scaphoid shape and potential vascular vulnerability. Both Type II capitate morphology and NUV are significant predisposing factors for PD. These findings offer valuable insights for identifying at-risk individuals and improving understanding of PD's multifactorial etiology. Diagnostic Level III.

Abstract Background: For patients with B-cell acute lymphoblastic leukemia (B-ALL), extramedullary relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) carries an extremely unfavorable prognosis. As a new immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable effects in refractory or relapsed B-ALL (r/r B-ALL). However, there is still a lack of evidence for its efficacy and safety in patients with extramedullary relapse after allo-HSCT. The aim of this study was to evaluate the safety and efficacy of allogeneic CAR-T in such high-risk populations. Method: We conducted a prospective clinical study, during which 7 patients with B-ALL who experienced extramedullary relapse after allo-HSCT were enrolled between October 2019 and January 2025. These patients all received allogeneic CD19 CAR-T cell therapy. We prospectively evaluated the safety, efficacy, and survival outcomes following CAR-T treatment. This study was registered at www.chictr.org.cn (No. ChiCTR2000036350). Results: This study included 7 patients with extramedullary relapse after allo-HSCT. Median age was 21 years (range: 15 - 46 years), and the median follow-up time was 415 days (range: 130 - 1320 days). The last follow-up was conducted until July 5, 2025. All the patients were classified as high-risk patients before transplantation. Four of them were Philadelphia chromosome/BCR-ABL positive (Ph+). The sites of extramedullary relapse included: 5 cases of central nervous system (among which 2 cases were accompanied by BCR-ABL molecular relapse in the bone marrow), 1 case of testicular relapse, and 1 case of extensive extramedullary relapse. The median interval from transplantation to extramedullary relapse was 628 days (44 - 1225 days). All patients received chemotherapy, radiotherapy or targeted therapy to reduce tumor burden before infusion. The infusion dose of CAR-T cells was 4 - 10 × 10⁶/kg. After infusion, one patient developed grade 3 cytokine release syndrome (CRS) and grade 4 immune effector cell-related neurotoxicity syndrome (ICANS), while the remaining patients did not experience grade 2 or higher CRS or ICANS. No patients developed graft-versus-host disease (GVHD), and all adverse events were resolved. In terms of therapeutic efficacy, one patient was considered unresponsive at the first assessment after infusion (54 days after infusion). The remaining 6 patients all achieved complete remission (CR) efficacy. The median duration of CR was 275 days (range: 120 - 1305 days). During the follow-up period, one patient suffered from central nervous system relapse again at 275 days post-infusion, while the other 5 maintained a continuous CR. The expansion of CAR-T cells in peripheral blood peaked between days 8 to 15 post-infusion, with a median peak of 1.90E+05 copies/μg DNA (range: 1.78E+04 – 3.18E+05 copies/μg DNA), and the longest duration of detectable expansion was 1320 days. Furthermore, CAR-T cells were detected in the cerebrospinal fluid of three patients, indicating their capability for targeted migration and central nervous system infiltration. Conclusion: Overall, allogeneic CAR-T therapy has demonstrated excellent safety and durable anti-leukemia effects in high-risk ALL patients with extramedullary relapse after transplantation.

Abstract Introduction: Teclistamab is the first FDA approved BCMA-directed bispecific antibody for the treatment of relapsed and refractory multiple myeloma (RRMM). With BCMA-targeting CAR-T therapies, cytokine release syndrome (CRS) is a risk factor for cardiotoxicity. Teclistamab was associated with fatal cardiovascular adverse events (CVAEs) in a recent US pharmacovigilance database analysis, but this analysis was limited by reporting bias. Therefore, the aim of our study is to conduct a multicenter study to define the real-world incidence of CVAEs in RRMM patients treated with teclistamab. Method We performed a retrospective multi-center cohort study of patients receiving teclistamab at 5 medical centers. Baseline oncologic and cardiovascular characteristics (including vital sign and echocardiographic data) were collected. Baseline cardiovascular disease (CVD) was defined as presence of coronary artery disease, congestive heart failure, severe or symptomatic valvular heart disease, or stroke at baseline. CVAE was collected and categorized based on CTCAE v5.0 by each institution. Major adverse cardiovascular event (MACE) was a composite outcome with any of the following: congestive heart failure, asymptomatic cardiomyopathy (interval LVEF drop &gt;10% to resultant LVEF less than 50%), coronary artery disease requiring intervention, stroke or cardiovascular death. Arrhythmia was a composite outcome with any of the following: atrial tachyarrhythmia, ventricular tachyarrhythmia or bradyarrhythmia. Median follow-up was calculated through reverse Kaplan-Meier method. Multivariable Cox regression analysis was used to define the relation between MACE and survival. Cause of death was categorized as myeloma-related death or non-myeloma-related deaths (i.e. CRS, infection or cardiovascular death). Cause-specific Cox regression was performed to define relationship between MACE and cause of death. Results In a cohort of 219 patients treated with teclistamab with median follow-up of 20.1 months, 7.3% (N=16) developed MACE, 7.3% (N=16) developed arrhythmia and 12.8% (N=28) developing any MACE or arrhythmia. MACE occurred at a median of 4.5 days (IQR 2.25-15.75 days) after teclistamab step-up. The incidence of MACE was 16.4% in patients with baseline CVD versus 2.7% in those without baseline CVD (p&lt;0.001). Patients who developed MACE had inferior ECOG performance status (PS) (PS &gt;=2: 62.5% vs. 27.7%; p=0.008). Additionally, baseline hemoglobin level (9 vs 10g/dL; p=0.072) was numerically lower in MACE, compared to no MACE. There was no difference in age, sex, bone marrow (BM) plasma cell burden, ferritin, C-reactive protein or LDH levels between MACE vs. no MACE group. Patients who developed MACE had lower baseline diastolic blood pressure (67.7 vs 73.8mmHg; p=0.041) and numerically lower LVEF (51.4 vs 59.3%; p=0.059; baseline echocardiogram performed in 86% of all cohort). Patients who developed MACE had similar incidences of CRS (Grade &gt;=2: 25.0 vs 16.7%; p=0.620) and immune effector cell-associated neurotoxicity (ICANS) grade 2 or higher (12.5 vs 7.5%; p=0.812). In multivariable Cox regression analysis, MACE was independently associated with inferior overall survival (HR 2.72; 95% CI 1.41-5.25; p=0.003), after adjusting for baseline CVD, age, high BM burden, extramedullary disease, and plasma cell leukemia. In cause-specific multivariable Cox regression analysis, MACE was independently associated with non-myeloma-related death (HR: 10.77 95% CI 4.39- 26.41; p&lt;0.001) but not with myeloma-related death (1.54; 95% CI 0.64- 3.70; p=0.336). Conclusion In conclusion, in this large, real-world multicenter study, we observed that MACE occurred in over 7% of patients following teclistamab for RRMM, typically within 2 weeks of initiation. MACE was significantly associated with increased non-myeloma-related mortality. In contrast to CAR-T therapy, CRS or ICANS were not associated with MACE, whereas majority of patients who developed MACE had ECOG PS &gt;=2 or baseline cardiovascular disease. More studies are necessary to define mechanisms and strategies to reduce these MACE and improve survival. Patients with baseline cardiovascular disease or poor performance status may benefit from cardiovascular optimization before and during teclistamab therapy.

Abstract Background: Pulmonary function tests, forced expiratory volume in 1 s (FEV₁) and diffusing capacity for carbon monoxide (DLCO), are integral to pre-transplant evaluation of allogeneic hematopoietic cell transplantation (HCT) candidates because they estimate the risk of early post-HCT death and respiratory failure. Interpretation has historically relied on race-specific Global Lung Function Initiative equations from 2012 (GLI-2012). In 2021 the Initiative released race-neutral equations (GLI-Global). The influence of adopting GLI-Global on risk stratification, outcome prediction, and transplant eligibility is unknown. Methods: We retrospectively analyzed 8808 adults who underwent first allogeneic HCT at four United States centers between 1999 and 2021. FEV₁ values were converted to z-scores with both GLI-2012 and GLI-Global, whereas DLCO z-scores were calculated with GLI-2017 which is a race neutral equation. Pulmonary impairment was graded with the Lung Function Score (LFS); each component [FEV₁ and DLCO] receives 1 to 6 points based on percent predicted (&gt; 80 % = 1, 70-79 % = 2, 60-69 % = 3, 50-59 % = 4, 40-49 % = 5, &lt; 40 % = 6) and the sum of 2 to 12 maps to grades I (2), II (3-5), III (6-9), and IV (10-12). Primary endpoints were non-relapse mortality (NRM) at 120 days and 2 years, intensive care unit admission, and invasive mechanical ventilation. Prediction was assessed with Cox proportional hazards models and Harrell c-statistics. Results: Switching to GLI-Global reclassified 4.2 % of patients (368 of 8808) across LFS strata. Reclassification was racially asymmetric: 12.2 % of Black patients moved to higher-risk grades whereas 3.9 % of White patients moved to lower-risk grades. C-statistics for FEV₁ z-scores were nearly identical with GLI-Global versus GLI-2012: 2-year NRM 0.544 vs 0.542, 120-day NRM 0.566 vs 0.568, intensive care admission 0.545 vs 0.538, and mechanical ventilation 0.605 vs 0.605; confidence intervals overlapped for every comparison. Continuous z-score models consistently outperformed categorical cut-offs for each outcome: 2-year NRM 0.544 vs 0.518, 120-day NRM 0.566 vs 0.523, intensive care admission 0.545 vs 0.515, and mechanical ventilation 0.605 vs 0.529; confidence intervals did not overlap for every comparison. The composite LFS outperformed models that used FEV₁ or DLCO alone. Extrapolating cohort reclassification rates to 38,606 adults aged 40 to 84 who received allogeneic HCTs reported to the Center for International Blood and Marrow Transplant Research between 2009 and 2018 predicts that 1521 patients, including 509 Black adults, would shift LFS grades and could face altered transplant eligibility. Conclusions: Race-neutral GLI-Global equations modestly change pulmonary risk categorization, disproportionately raising scores for Black HCT candidates, yet maintain predictive accuracy for early mortality, respiratory failure, and intensive care use. Continuous dual-variable models and the composite LFS provide superior prediction. Although race-neutral interpretation aligns with current society guidelines, its tendency to classify Black individuals as higher risk highlights the need for refined continuous models that limit unnecessary reclassification and increased disparities in transplant eligibility.