Treatment of Chronic Lymphocytic Leukemia
Treatment of Chronic Lymphocytic Leukemia
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.
Inclusion Criteria:

 -  patients with CLL