Clinical Advances in Hematology & Oncology最新文献

Molecular residual disease (MRD) assays using circulating tumor DNA (ctDNA) have the potential to detect colorectal cancer recurrence earlier than current standard-of-care surveillance techniques, such as carcinoembryonic antigen measurement and follow-up with computed tomography. Residual cancer cells that increase the risk of disease recurrence and the ctDNA released from these cells into the bloodstream are not detectable through standard imaging but can be detected with MRD tests. Two types of MRD assays developed for use in oncology are tumor-informed, which detect mutations specific to a patient's tumor, and tumor-naive, which detect known ctDNA sequences that are not specific to a patient's tumor genomics. The tumor-informed MRD test has high sensitivity but requires tumor sequencing that takes longer to process, whereas the tumornaive MRD test has a shorter turnaround time but a lower sensitivity. In prospective studies of these tests, patients with ctDNA-positive results were more likely to experience disease recurrence after surgery or definitive therapy than patients with ctDNA-negative results. Multiple platforms are already in clinical use or being developed as part of research studies. One such platform using the Oncodetect MRD test has confirmed the value of ctDNA testing and its association with recurrence-free survival at multiple timepoints (postsurgical, post-definitive therapy, and surveillance) in patients with colorectal cancer.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder in which a somatic mutation in PIGA leads to reduced or absent expression of glycosylphosphatidylinositol-anchored complement regulatory proteins. PNH presents with the central manifestations of complement-mediated hemolytic anemia, bone marrow failure, and thrombosis. The introduction of terminal complement inhibitors that block complement protein 5 (C5) has revolutionized the management of PNH by reducing the risk for thrombosis, extending survival to be similar to that of healthy controls, and improving quality of life. C5 inhibitors approved by the US Food and Drug Administration (FDA) include eculizumab (administered intravenously every 2 weeks), ravulizumab (administered intravenously every 8 weeks), and, most recently, crovalimab (administered subcutaneously every 4 weeks). Given the chronic nature and life-threatening complications of PNH, longterm efficacy and safety data of treatment approaches are invaluable. The most extensive experience has been gained with eculizumab, and now 6-year data with ravulizumab point to its durable control of terminal complement activity and intravascular hemolysis. Although terminal complement inhibitors effectively control intravascular hemolysis, approximately 30% of patients receiving C5 inhibitors develop clinically significant extravascular hemolysis with ongoing transfusion requirements or symptomatic anemia. Upstream complement inhibitors that inhibit components of the alternative complement system have been developed with the goal of addressing both intravascular and extravascular hemolysis. The C3 inhibitor pegcetacoplan (administered subcutaneously twice weekly) and the factor B inhibitor iptacopan (administered orally twice daily), both used as single agents, have demonstrated effective control of hemolysis with increased hemoglobin and transfusion avoidance in both C5 inhibitor-naive and C5 inhibitor-experienced patients with clinically significant extravascular hemolysis. The factor D inhibitor danicopan (administered orally 3 times a day) is used as an add-on to ravulizumab or eculizumab and offers a combination approach by targeting both terminal complement and the alternative pathway. Breakthrough hemolysis in the event of a strong complement trigger is possible on any complement inhibitor, but these breakthrough events could be more severe with alternative pathway inhibitor monotherapy. Rates of breakthrough hemolysis and whether they differ between the alternative pathway inhibitors remain to be determined in the real-world setting.