Cardiovascular Toxicities of BTK Inhibitors in Chronic Lymphocytic Leukemia: JACC: CardioOncology State-of-the-Art Review.

Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed, shifting from cytotoxic chemotherapy to targeted therapies. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL and are increasingly applied in many other malignancies. However, ibrutinib, the first BTK inhibitor approved, is associated with serious toxicities, including atrial fibrillation in up to 38% of patients, ventricular arrhythmias, and other cardiovascular toxicities. Emerging data suggest several newer BTK inhibitors (eg, acalabrutinib, zanubrutinib) are still associated with cardiotoxic risks. This review examines the current state of evidence, including incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities with BTK inhibitors and other CLL therapies. We specifically focus on atrial fibrillation, ventricular arrhythmias/sudden death, hypertension, heart failure, bleeding, and stroke. We also touch on other emerging BTK therapies (eg, pirtobrutinib). Finally, we highlight key unanswered questions and future directions of research.

A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by stem cell transplant, targeted approaches such as the BTK inhibitor ibrutinib, and CD19 chimeric antigen receptor (CAR) T cells. CD74 is a nonpolymorphic type II integral membrane glycoprotein identified as an MHC class II chaperone and a receptor for macrophage migration inhibitory factor. Our group previously reported on CD74's abundant expression in MCL and its ability to increase via pharmacological inhibition of autophagosomal degradation. Milatuzumab, a fully humanized anti-CD74 monoclonal antibody, demonstrated significant activity in preclinical lymphoma models but failed to provide meaningful benefits in clinical trials mainly due to its short half-life. We hypothesized that targeting CD74 using a CAR-T cell would provide potent and durable anti-MCL activity. METHODS: We engineered a second generation anti-CD74 CAR with 4-1BB and CD3ζ signaling domains (74bbz). Through in silico and rational mutagenesis on the scFV domain, the 74bbz CAR was functionally optimized for superior antigen binding affinity, proliferative signaling, and cytotoxic activity against MCL cells in vitro and in vivo. RESULTS: Functionally optimized 74bbz CAR-T cells (clone 42105) induced significant killing of MCL cell lines, and primary MCL patient samples including one relapse after commercial CD19 CAR-T cell therapy with direct correlation between antigen density and cytotoxicity. It significantly prolonged the survival of an animal model established in NOD-SCIDγc-/- (NSG) mice engrafted with a human MCL cell line Mino subcutaneously compared to controls. Finally, while CD74 is also expressed on normal immune cell subsets, treatment with 74bbz CAR-T cells resulted in minimal cytotoxicity against these cells both in vitro and in vivo. CONCLUSIONS: Targeting CD74 with 74bbz CAR-T cells represents a new cell therapy to provide a potent and durable and anti-MCL activity.

Nocturia is an Independent Predictor of Abdominal Aortic Calcification in Women: Results from the National Health and Nutrition Examination Survey.

Nocturia is generally considered a urological condition, but may be an indicator of cardiovascular disease, as prior studies have found associations with cardiovascular risk factors as well as clinical and subclinical markers of coronary artery disease. This study aimed to explore potential associations between nocturia and abdominal aortic calcification (AAC). We analyzed 2013-2014 National Health and Nutrition Examination Survey dual energy x-ray absorptiometry-derived AAC data and concurrent interview data on kidney conditions from respondents aged 40-80 years. AAC was defined as a score ≥ 1 on the 24-point semi-quantitative AAC scale. Nocturia was defined as an average of ≥ 2 voids per night. Three incremental multivariate logistic regression models controlling for (1) age, (2) sex, race, and BMI, and (3) hypertension, diabetes mellitus, and smoking history were used to determine whether nocturia predicted AAC. These models were and modified to exclude age and/or sex to perform age- and/or sex-specific sub-analyses, respectively. Complete data were available from 2,945 participants (29.1% AAC, 31.4% nocturia). On univariate analysis, the association between nocturia and AAC was significant in women (OR 1.77 [95% CI 1.37-2.29], p < 0.001), but not in men (1.14 [0.74-1.76], p = 0.531). Multivariate analysis showed nocturia was an independent predictor of AAC in women in Models I-II (ORs 1.49-1.58, p ≤ 0.032) but not Model III (1.37 [0.90-2.09], p = 0.133). Stratification by age revealed a strong univariate association among women aged 50-59 (3.88 [1.97-7.61], p < 0.001), which persisted across all multivariate models (ORs 4.05-4.41, p ≤ 0.001). The presence of nocturia is an important clue of AAC in women, especially those middle-aged.