Hematology
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For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. ⋯ Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies.
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The lack of a strong evidence base to guide the management of adults with sickle cell disease (SCD) makes it difficult for patients to receive high quality care outside of specialty centers. As there is a dearth of providers with sickle cell expertise, the purpose of this article is to identify some of the key things every provider who manages the care of adults with SCD should know. ⋯ We have chosen topics for which there is a limited evidence base but which have significant clinical consequences if left unrecognized or poorly managed. The topics that will be addressed include chronic pain, neurocognitive dysfunction, renal disease, venous thromboembolism, and avoiding the inappropriate use of red cell transfusions.
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Substantial progress has been made in our understanding of the risks and benefits of RBC transfusion through the performance of large clinical trials. More than 7000 patients have been enrolled in trials randomly allocating patients to higher transfusion thresholds (∼9-10 g/dL), referred to as liberal transfusion, or lower transfusion thresholds (∼7-8 g/dL), referred to as restrictive transfusion. The results of most of the trials suggest that a restrictive transfusion strategy is safe and, in some cases, superior to a liberal transfusion strategy. However, in patients with myocardial infarction, brain injury, stroke, or hematological disorders, more large trials are needed because preliminary evidence suggests that liberal transfusion might be beneficial or trials have not been performed at all.
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Relapsed and refractory leukemias pose substantial challenges in both children and adults, with very little progress being made in more than a decade. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells has emerged as a potent therapy with an innovative mechanism. ⋯ Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome, posing a unique challenge for toxicity management. Further studies are necessary to identify additional targets, standardize approaches to cytokine release syndrome management, and determine the durability of remissions.