Cellular Therapies in Chronic Lymphocytic Leukemia and Richter’s Transformation: Recent Developments in Chimeric Antigen Receptor T-Cells, Natural Killer Cells, and Allogeneic Stem Cell Transplant

Cellular therapies can be viewed as both the newest and oldest techniques for treating chronic lymphocytic leukemia (CLL) and Richter’s transformation (RT). On one hand, allogeneic hematopoietic stem cell transplantation (alloHSCT) has been available for decades, though its use is diminishing with the increasing availability of effective novel targeted agents, especially in CLL. Among newer techniques, chimeric antigen receptor T-cells (CAR-T) have demonstrated astounding efficacy in several hematologic malignancies, leading to FDA approval and use in clinical practice. However, though CLL is the earliest disease type for which CAR-T were studied, development has been slower and has yet to lead to regulatory approval. Owing partially to its rarity but also due to the aggressive behavior of RT, CAR-T in RT have only been minimally explored. Here, we will focus on the applications of cellular therapies in CLL and RT, specifically reviewing more recent data related to alloHSCT in the novel-agent era and CAR-T cell development in CLL/RT, focusing on safety and efficacy successes and limitations. We will review strategies to improve upon CAR-T efficacy and discuss ongoing trials utilizing CAR-T in CLL/RT, as well as emerging technologies, such as allogeneic CAR-T and natural killer CAR (CAR NK) cells

Cellular Therapies in Chronic Lymphocytic Leukemia and Richter’s Transformation: Recent Developments in Chimeric Antigen Receptor T-Cells, Natural Killer Cells, and Allogeneic Stem Cell Transplant

Cellular therapies can be viewed as both the newest and oldest techniques for treating chronic lymphocytic leukemia (CLL) and Richter's transformation (RT). On one hand, allogeneic hematopoietic stem cell transplantation (alloHSCT) has been available for decades, though its use is diminishing with the increasing availability of effective novel targeted agents, especially in CLL. Among newer techniques, chimeric antigen receptor T-cells (CAR-T) have demonstrated astounding efficacy in several hematologic malignancies, leading to FDA approval and use in clinical practice. However, though CLL is the earliest disease type for which CAR-T were studied, development has been slower and has yet to lead to regulatory approval. Owing partially to its rarity but also due to the aggressive behavior of RT, CAR-T in RT have only been minimally explored. Here, we will focus on the applications of cellular therapies in CLL and RT, specifically reviewing more recent data related to alloHSCT in the novel-agent era and CAR-T cell development in CLL/RT, focusing on safety and efficacy successes and limitations. We will review strategies to improve upon CAR-T efficacy and discuss ongoing trials utilizing CAR-T in CLL/RT, as well as emerging technologies, such as allogeneic CAR-T and natural killer CAR (CAR NK) cells

Clonal Hematopoiesis and the Heart: a Toxic Relationship

Purpose of reviewClonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes.Recent findingsA combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1β and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1β or JAK2 signaling are potential avenues for preventing CH-caused cardiovascular morbidity and mortality