Sickle cell disease (SCD) is a prevalent genetic disorder caused by a mutation in the beta-globin gene. Hyperhemolysis (HS) is a severe complication involving the rapid destruction of both transfused and endogenous red blood cells, commonly found in SCD. This literature review explores the clinical presentation, diagnosis, pathogenesis, and management of HS in SCD. HS can manifest acutely or in a delayed manner, complicating diagnosis due to overlapping symptoms and varying reticulocyte responses. Immunohematological assessments often reveal delayed positivity in direct antiglobulin tests and antibody screens. HS typically presents severe anemia, jaundice, hemoglobinuria, and hemodynamic instability. Diagnostic markers include elevated bilirubin and lactate dehydrogenase levels alongside a reduced reticulocyte count. The management of HS is primarily empirical, with no clinical trials to support standardized treatment protocols. First-line treatments involve steroids and intravenous immunoglobulins (IVIG), which modulate immune responses and mitigate hemolysis. Refractory cases may require additional agents such as rituximab, eculizumab, tocilizumab, and, in some instances, plasma exchange or erythropoietin-stimulating agents. Novel therapeutic approaches, including bortezomib and Hemopure, have shown promise but require further investigation. Current management strategies are empirical, underscoring the need for robust clinical trials to establish effective treatment protocols that ultimately improve outcomes for SCD patients experiencing HS.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Chimeric antigen receptor T-cell (CART) therapy is a novel therapeutic modality utilized for managing relapsed/refractory hematologic cancers. This approach entails the genetic modification of either autologous or allogeneic T-cells to incorporate chimeric antigen receptor (CAR) proteins, enabling them to target specific proteins present on the surface of cancer cells and causing cytotoxicity. Despite its promising therapeutic outcomes, there is a notable drawback wherein these modified cells may also attack normal tissue cells expressing similar surface proteins. This phenomenon of cross-reactivity often leads to adverse events (AEs), resulting in significant mortality and morbidity. This chapter focuses on the assessment and management of CART therapy-related toxicities.