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CLL is a disease of the elderly, identifying effective therapies with better toxicity profiles is thus a high priority, and targeted therapies may allow attainment of this goal.
Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the extensive accumulation of monoclonal, relatively mature CD5+CD23+ B lymphocytes in lymphoid organs, bone marrow, and peripheral blood. CLL cells accumulate because of defective apoptosis, which extends survival. CLL is a heterogeneous disease. Chemoimmunotherapy is the standard front-line approach for patients younger than 65 years with CLL, with the combination of fludarabine, cyclophosphamide, and rituximab used most commonly. Some CLL patients do not respond well to routine chemoimmunotherapy. Despite recent advances in the treatment of CLL by use of modern chemoimmunotherapy, the disease remains incurable for most patients with the exception of those who have the option of an allogeneic transplantation. However, treatments with chemoimmunotherapy are associated with significant toxicities and sustained immunosuppression, and the rates of myelosuppression and infection are high. Such complications are more frequent and more severe in patients older than 65 years because of reduced marrow reserve, and presence of comorbidities. Because CLL is a disease of the elderly, identifying effective therapies with better toxicity profiles is thus a high priority, and targeted therapies may allow attainment of this goal.
CLL tumor cells are highly dependent on the microenvironment where cytokines (eg, CD40L, BAFF, IL-4, IL-6), and contact (eg, stromal cells) promote cell activation and proliferation, and also resistance to spontaneous and drug-mediated apoptosis. Many of these microenvironment-activated pathways merge with TSPs exported by XPO1. XPO1 is therefore a highly attractive molecular target to explore in CLL, because it impacts multiple antitumor and growth suppressive signaling pathways that are dysregulated in this disease.
The investigators therefore hypothesized that a selective XPO1 inhibitor would show efficacy with an acceptable therapeutic index in CLL and other diseases. Indeed, XPO1 inhibition in normal cells (ie, possessing an intact genome) leads to transient cell cycle arrest without cytotoxicity, followed by fast recovery after the drug is removed. To date, efforts to clinically pharmacologically inhibit XPO1 have been unsuccessful because of off-target effects. A selective XPO1 antagonist may allow targeting of the TSPs axes in tumor cells.
Observational Model: Case-Crossover, Time Perspective: Cross-Sectional
Leukemia, Lymphocytic, Chronic, B-Cell
Active, not recruiting
Peking University People's Hospital
Published on BioPortfolio: 2016-05-02T22:08:21-0400
Chronic lymphocytic leukemia. B-cell chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in the Western Hemisphere, accounting for ~25% of all leukemia's. It represents a ...
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A chronic leukemia characterized by abnormal B-lymphocytes and often generalized lymphadenopathy. In patients presenting predominately with blood and bone marrow involvement it is called chronic lymphocytic leukemia (CLL); in those predominately with enlarged lymph nodes it is called small lymphocytic lymphoma. These terms represent spectrums of the same disease.
A lymphoid leukemia characterized by a profound LYMPHOCYTOSIS with or without LYMPHADENOPATHY, hepatosplenomegaly, frequently rapid progression, and short survival. It was formerly called T-cell chronic lymphocytic leukemia.
A chronic leukemia characterized by a large number of circulating prolymphocytes. It can arise spontaneously or as a consequence of transformation of CHRONIC LYMPHOCYTIC LEUKEMIA.
A basic helix-loop-helix transcription factor that plays a critical role in HEMATOPOIESIS and as a positive regulator in the differentiation of ERYTHROID CELLS. Chromosome translocations involving the TAL-1 gene are associated with T-CELL ACUTE LYMPHOCYTIC LEUKEMIA.
An anti-CD52 ANTIGEN monoclonal antibody used for the treatment of certain types of CD52-positive lymphomas (e.g., CHRONIC LYMPHOCYTIC LEUKEMIA; CUTANEOUS T-CELL LYMPHOMA; and T-CELL LYMPHOMA). Its mode of actions include ANTIBODY-DEPENDENT CELL CYTOTOXICITY.
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