Kaur, Harbir

Chimeric antigen receptor (CAR)-based therapies have become an integral part of modern cancer care, delivering durable responses in patients with otherwise refractory hematologic malignancies. As their use has expanded, it has become increasingly clear that these immune-based treatments exert important effects on the cardiovascular system. Rather than reflecting isolated cardiac injury, CAR-associated cardiovascular complications arise from a broader inflammatory process in which immune activation, cytokine release, endothelial dysfunction, and myocardial stress are closely interconnected. Pro-inflammatory mediators such as interleukin-6, interleukin-1β, tumor necrosis factor-α, and interferon-γ play central roles in shaping these responses, particularly during cytokine release syndrome. From a clinical perspective, cardiovascular manifestations often include hypotension, arrhythmias, and transient reductions in left ventricular function, with more severe presentations occurring in patients who develop high-grade inflammatory toxicity. At the same time, advances in immune engineering are reshaping how these platforms are viewed, extending their relevance beyond toxicity alone. Preclinical studies now suggest that CAR-based approaches may be adapted to modulate cardiac fibrosis and promote myocardial repair, highlighting a potential shift from purely oncologic applications toward broader cardiovascular benefit. Placing these developments within a cardio-oncology framework emphasizes the need for careful cardiovascular assessment, longitudinal monitoring, and close collaboration between specialties.

The therapeutic landscape of hematologic malignancies has undergone a paradigm shift with the increasing incorporation of targeted therapies, including inhibitors of vascular endothelial growth factor (VEGF) signaling. While VEGF-directed agents have historically been developed and deployed in solid tumors, their application in hematologic cancers—particularly multiple myeloma, select leukemias, and rare lymphomas—has expanded in investigational and clinical settings. VEGF is fundamental to angiogenesis, maintenance of endothelial integrity, and regulation of vascular tone. As a result, therapeutic inhibition of VEGF signaling is associated with a characteristic spectrum of cardiovascular adverse effects. These include hypertension, endothelial dysfunction, heart failure, thromboembolic complications, and renal injury, all of which present important clinical challenges in patients with hematologic malignancies. This population frequently has additional vulnerability due to factors such as cytopenias, preexisting renal impairment, and prior exposure to cardiotoxic anticancer therapies. This review aims to provide a cardio-oncology–oriented overview of VEGF biology, the range of VEGF-targeted agents used in hematologic cancers, and the underlying mechanisms driving their cardiovascular toxicities.

Advances in cancer therapeutics have substantially improved survival across multiple malignancies but have concurrently increased the burden of cancer therapy–related cardiovascular toxicity, establishing cardio-oncology as an essential discipline situated at the interface of oncology and cardiovascular medicine. Despite growing incorporation of cardiac imaging and circulating cardiac biomarkers into surveillance strategies, current approaches remain limited by modest specificity, heterogeneous risk profiles, and inconsistent translation into effective cardioprotective interventions. This review synthesizes contemporary evidence on the biological mechanisms underlying cancer therapy–related cardiovascular toxicity and critically evaluates the current role and limitations of established cardiac biomarkers, including high-sensitivity cardiac troponins and natriuretic peptides, in risk stratification and early injury detection. We further examine why many cardioprotective clinical trials have yielded neutral or modest results, highlighting signal dilution arising from low-risk populations, endpoint heterogeneity, and timing mismatches between injury biology and intervention. This review advances a precision cardio-oncology framework by integrating tumor-derived liquid biopsy platforms—such as circulating tumor DNA, tissue-specific cell-free DNA, and extracellular vesicles—with cardiac biomarkers to provide a biologically contextualized assessment of cardiovascular risk. Tumor-derived biomarkers may reflect treatment intensity, systemic inflammatory burden, and cardiotoxic susceptibility, thereby enhancing the interpretation of cardiac biomarker signals and refining patient selection for targeted cardioprotective strategies.

Abstract Background: Patients with myelodysplastic syndromes (MDS) are at heightened risk for severe infections, including sepsis, due to underlying cytopenias and immune dysregulation. Hospital-level characteristics, including size and available resources, may influence clinical outcomes in these patients, but data remain limited. This study examines the association between hospital bed size and sepsis-related complications in patients with MDS using a nationally representative dataset. Methods: We conducted a retrospective cohort analysis using the National Inpatient Sample (NIS) from 2016 to 2022, identifying adult hospitalizations with co-diagnoses of MDS and sepsis. Hospitalizations were stratified by hospital bed size: small (n = 15,490), medium (n = 22,815), and large (n = 40,245). Multivariable logistic regression, adjusted for patient demographics, comorbidities, and hospital characteristics, was used to assess associations between hospital bed size and eight clinical outcomes: in-hospital mortality, septic shock, acute renal failure, respiratory failure, encephalopathy, disseminated intravascular coagulation (DIC), Clostridioides difficile infection (CDI), and fungal sepsis. Results: Compared to small hospitals, patients treated at large hospitals had significantly higher odds of in-hospital mortality (OR 1.43, p < 0.001), septic shock (OR 1.25, p < 0.001), acute renal failure (OR 1.10, p < 0.001), encephalopathy (OR 1.11, p = 0.004), DIC (OR 1.48, p = 0.007), and fungal sepsis (OR 2.13, p = 0.028). Medium-sized hospitals were also associated with increased odds of mortality (OR 1.16, p = 0.021) and septic shock (OR 1.13, p = 0.038). No statistically significant differences were found in rates of CDI across hospital sizes. Respiratory failure showed a borderline association in medium hospitals (OR 1.05, p = 0.082) but not in large hospitals. Conclusion: Hospital bed size is independently associated with important variations in sepsis-related outcomes among patients with MDS. Large hospitals demonstrated significantly increased odds of multiple complications and mortality, possibly reflecting referral bias, higher disease acuity, or institutional coding practices. These findings underscore the importance of hospital-level factors in evaluating outcomes and resource planning for high-risk hematologic populations. Keywords: Myelodysplastic syndromes, hospital bed size, sepsis, mortality, ICU complications, NIS

Abstract Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders often complicated by infections due to cytopenias. Sepsis is a frequent cause of hospitalization and mortality in MDS patients. Neutropenia, a common feature in MDS, may predispose patients to specific infectious complications, but its impact on sepsis-related outcomes remains poorly characterized. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) database from 2016 to 2022. Adult hospitalizations with co-diagnoses of MDS and sepsis were identified using ICD-10-CM codes. Patients were stratified based on the presence or absence of neutropenia. Multivariable logistic regression models were used to evaluate the association between neutropenia and specific in-hospital outcomes, including Clostridioides difficile infection, fungal sepsis, and disseminated intravascular coagulation (DIC). Models were adjusted for age, sex, comorbidities, hospital characteristics, and illness severity. Results: A total of 78,549 hospitalizations involving MDS patients with sepsis were identified, including 11,295 (14.4%) with neutropenia. Neutropenic patients had significantly higher odds of C. difficile infection (adjusted odds ratio [aOR] 1.61, 95% CI 1.30–1.99, p < 0.001) and fungal sepsis (aOR 2.08, 95% CI 1.22–3.54, p = 0.007) compared to those without neutropenia. However, neutropenia was not significantly associated with DIC (aOR 0.84, 95% CI 0.59–1.19, p = 0.322). Conclusion: In this large national cohort, neutropenia was associated with a significantly increased risk of C. difficile infection and fungal sepsis among MDS patients hospitalized with sepsis. These findings highlight the need for early recognition and targeted antimicrobial strategies in neutropenic MDS patients. No significant association was observed between neutropenia and DIC. Future studies should explore preventive strategies and risk stratification tools tailored to this high-risk population. Keywords: Myelodysplastic syndromes, neutropenia, sepsis, NIS, Clostridioides difficile, fungal sepsis, outcomes

Abstract Background: RUNX1 mutations are established high-risk features in acute myeloid leukemia (AML), associated with poor response to induction therapy and reduced overall survival (OS). Current prognostic models, including the ELN 2022 classification, incorporate RUNX1 mutation status but are based largely on cohorts of European ancestry. This raises concerns about their generalizability to underrepresented populations, particularly African American patients, who continue to experience worse outcomes in AML across treatment settings. Methods: We analyzed publicly available datasets, including TCGA-LAML, Beat AML, and a recent multi-omic study of 100 African American AML patients (Stiff et al., Nat Genet 2024). We evaluated RUNX1 mutation frequency, OS outcomes, and co-mutation patterns, stratified by race. To contextualize survival differences by ancestry, we performed a survival analysis of adult AML patients using the SEER 17 registries (2010–2020), accessed through SEER*Stat. Kaplan-Meier estimates and median OS were compared by race using disease-specific survival. Results: RUNX1 mutations were present in approximately 10–15% of AML cases and consistently associated with inferior OS (median 16–24 months) in both de novo and AML-MRC subsets. Co-mutations in DNMT3A and TET2 further worsened the prognosis. In the African American cohort described by Stiff et al., the frequency of RUNX1 mutations was similar to that in White patients; however, African American patients showed enrichment for IDH2, RAS, and WT1 mutations and lower incidence of NPM1 mutations. Despite comparable mutation rates, African American patients demonstrated significantly worse OS, even under standardized treatment. SEER 17 survival analysis of 5,932 AML cases (683 African American) confirmed shorter median OS in African American patients compared to non-African American patients (10.4 vs. 15.7 months, p<0.01).Conclusions: RUNX1 mutations confer adverse prognosis in AML, but current risk models may not adequately reflect risk in African American patients due to differing co-mutation patterns and underrepresentation in genomic datasets. These findings highlight the need for ancestry-aware risk stratification and inclusive genomic profiling to reduce disparities in AML outcomes. References: Lew-Derivry et al. Leukemia. 2023 Jalili et al. PMCID: PMC5980915 Stiff et al. Nat Genet. 2024 Bhatnagar et al. PMCID: PMC7933110 Tang et al. Blood. 2009 Mendler et al. JCO. 2012 He et al. Scand J Clin Lab Invest. 2020 Döhner et al. Blood. 2022. PMID: 35926292