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Cellular-redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, are rapidly changing the treatment landscape of hematologic malignancies and solid tumor malignancies. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the disease specialist, and the immune effector cell provider will be needed to provide optimal care longitudinally for any patient. I will discuss practical ways for any program to deliver these therapies and how future advances may widen availability beyond just a few centers.Despite the effectiveness of chemoimmunotherapy (CIT), in most cases the clinical course of chronic lymphocytic leukemia (CLL) is characterized by consecutive episodes of disease progression and need for therapy. Treatment possibilities for patients with CLL in whom CIT fails whose disease progresses after initial CIT include pathway inhibitors (PIs) and, for selected patients, cellular therapy (ie, allogeneic stem cell transplant, chimeric antigen receptor T cells). PIs (ie, Bruton tyrosine kinase inhibitors, phosphatidylinositol 3-kinase inhibitors, and BCL2 inhibitors) are revolutionizing the treatment of CLL. https://www.selleckchem.com/products/Erlotinib-Hydrochloride.html PIs have proved to be more effective than CIT, both as upfront therapy and for relapsed/refractory disease, largely because they may overcome the negative impact of adverse biomarkers (eg, TP53 aberrations, unmutated IGHV) on outcomes and because of their acceptable toxicity. In this article, the management of patients with relapsed/refractory CLL is discussed, with a particular emphasis on the role of PIs.As CAR T-cell therapy has advanced in B-cell acute lymphoblastic leukemia, research is now underway to develop similar therapies for other lymphoid and myeloid malignancies for pediatric patients. Barriers, including antigen selection and on-target/off-tumor toxicity, have prevented the rapid development of immune-based therapies for T-lineage and myeloid malignancies. More recently, unique strategies have been developed to overcome these barriers, with several products advancing to clinical trials. For T-lineage diseases, targets have focused on CD5, CD7, and CD38, whereas myeloid disease targets have predominately focused on CD123, CD33, and, more recently, CLL-1. This review provides a comprehensive overview of these targets and approaches to overcoming safety concerns in the development of CAR T-cell therapies for pediatric patients with T-lineage and myeloid malignancies.The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.Treatment of acute leukemia has been delivered predominantly in academic and larger leukemia treatment centers with the infrastructure and staff needed to manage patients receiving complex therapeutic regimens and supportive care. However, in recent years, several oral agents and less-myelosuppressive regimens were approved, making it possible for these patients to receive therapy in smaller community hospitals and oncology office practices. In this review, we discuss the optimum community setting, type of patient who can be treated, agents that can be applied, and an appropriate clinical circumstance in which a referral to a tertiary center should be made.The low prevalence of pulmonary embolism (PE) among pregnant patients presenting with suspected PE implies that most of these patients will be found not have the disease. Given this low prevalence, excluding PE in this population has necessitated the use of sensitive and specific diagnostic imaging, such as computed tomography pulmonary angiography or ventilation-perfusion scanning. Recent studies suggest that a clinical prediction rule with D-dimer testing can also be used to exclude a subset of pregnant patients with suspected PE without the need for diagnostic imaging. The YEARS criteria, which consist of clinical signs and symptoms of deep venous thrombosis, hemoptysis, and PE as the most likely diagnosis (a subjective variable), combined with selective D-dimer levels, seem to safely exclude up to one-third of these patients without imaging. The revised Geneva rule using objective variables, combined with nonpregnancy cutoffs for D-dimer levels, offers some promise, although fewer patients avoided imaging (14%).
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