Best practice & research. Clinical haematology
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Clonal Hematopoiesis is defined as the presence of mutations in peripheral blood in the absence of myeloid malignancies and is thought to occur as a normal part of ageing due to the fitness advantage conferred by these mutations in an ageing hematopoietic compartment. Therapy related myeloid neoplasms are malignancies that occur after exposure to chemotherapy/radiation and are associated with poor survival. Clonal hematopoiesis mutations represent a pre malignant state that can be triggered by exposure to cytotoxic damage and rapid hematopoietic stem cell expansion. We discuss in this review clinical evidence of association of clonal hematopoiesis with risk of therapy related myeloid neoplasms, the underlying mechanisms of clonal expansion under different cellular stresses and recommendations on clinical follow up of patients with clonal hematopoiesis including possible strategies for prevention of therapy related myeloid neoplasms.
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Best Pract Res Clin Haematol · Sep 2018
ReviewThe promise of CAR T-cell therapy in aggressive B-cell lymphoma.
Relapsed or refractory aggressive B-cell lymphoma has an extremely poor prognosis and efforts to develop novel therapies for these patients have failed for almost four decades until the advent of chimeric antigen receptor (CAR) T-cell therapy. Within the last one year, two anti-CD19 CAR T-cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, were approved by the United States Food and Drug Administration for the treatment of relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy based on multicenter single-arm phase two clinical trials. Here, we will discuss the different components of the CAR construct and their mechanisms of action, the role of conditioning chemotherapy, the efficacy and toxicity observed with anti-CD19 CAR T-cell therapies in aggressive B-cell lymphomas, and emerging strategies to further improve the safety and efficacy of these highly promising approaches.
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Best Pract Res Clin Haematol · Jun 2018
ReviewCARs and other T cell therapies for MM: The clinical experience.
Harnessing the endogenous immune system to eliminate malignant cells has long been an intriguing approach. After considerable success in the treatment of B-cell acute lymphoblastic leukemia, chimeric antigen receptor (CAR)-modified T cells have entered early clinical evaluation in the field of multiple myeloma (MM). The choice of suitable non-CD19 target antigens is challenging and a variety of myeloma-associated surface molecules have been under preclinical investigation. ⋯ The trials differ in receptor constructs, patient selection, dosing strategies and conditioning chemotherapy and will thus pave the way to eventually define the optimal parameters. Other sources for autologous T-cell therapy of MM include affinity-enhanced T-cell receptor-modified cells and marrow infiltrating lymphocytes. In summary, adoptive T-cell transfer for the treatment of MM is still in its infancy, but if early response rates indicate durability, will be a paradigm changing therapeutic modality for the treatment of MM.
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B-cell non-Hodgkin's lymphoma (NHLs)is a very heterogonous malignancy with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) as the most common subtypes. Standard treatment with anti-CD20 based chemoimmunotherapy is usually very effective for disease control. ⋯ Adoptive therapy with chimeric antigen receptor (CAR) T-cells is a new paradigm for effective treatment of poor prognosis lymphomas. Here we review the biology of poor risk DLBCL and FL, the rationale for CAR T-cell therapy in malignant lymphoma and the efficacy/toxicity profile of CD19 directed CAR T cell therapy for DLBCL and FL from early single center studies to multicenter/global clinical trial with different CAR T cell constructs.
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Best Pract Res Clin Haematol · Dec 2017
ReviewWhich new agents will be incorporated into frontline therapy in acute myeloid leukemia?
For 4 decades, new agents had not been permanently approved for use in treating acute myeloid leukemia (AML). The long dry spell was broken in 2017, however, with the approval of several agents: midostaurin for addition to chemotherapy in mutant FLT3 patients undergoing intensive chemotherapy, enasidenib in advanced mutant IDH2 patients, CPX-351 in secondary AML patients, and gemtuzumab ozogamicin in conjunction with standard chemotherapy in AML. This review surveys the use of tyrosine kinase inhibitors to treat patients with mutant FLT3 AML, mutant KIT AML, as well as IDH inhibitors and explores some questions regarding their integration into the treatment armamentarium for AML.