Blood
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Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell-specific antigen CD19. ⋯ Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.
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Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. ⋯ Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.
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Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. ⋯ Metagenomic next-generation sequencing did not reveal additional significant pathogens. Our study demonstrated that approximately half of patients with IPS had pathogens detected in BAL, and pathogen detection was associated with increased mortality. Thus, an expanded infection detection panel can significantly increase the diagnostic precision for idiopathic pneumonia.
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In this issue of Blood, Chalandon et al report the results of a prospective randomized study comparing standard vs less-intensive chemotherapy, both combined with imatinib, for patients with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). They show that the less-intensive therapy reduces early mortality without impairing efficacy, resulting in a significantly higher hematologic complete remission (CR) rate and an equivalent major molecular response (MMolR) rate.