Resistance to chemotherapy-induced apoptosis in CLL is associated with overexpression of antiapoptotic proteins induced by signals from the microenvironment. In vitro, dasatinib effectively inhibits expression of anti-apoptotic regulators and restores fludarabine sensitivity in activated CLL.
The aim of this study was to evaluate efficacy of one cycle of dasatinib monotherapy (100 mg/day, days 1-28) followed by combination of dasatinib with fludarabine (40 mg/m(2)/day, days 1-3 every 28 day) for a total of it cycles in fludarabine-refractory. The primary endpoint was overall response rate according to the IWCLL'08 criteria.
20 patients were enrolled: 18 completed at least one cycle of treatment of which 67% finishsed at Pact 2 cycles of combination treatment. 3 of these 18 patients reached a format PR (16,7%). Majority of patients obtained some reduction in lymph node (LN) size. Most frequent toxicity was related to myelosuppression.
NF-kappa B RNA expression levels of circulating CLL cells decreased whereas the levels of pro-apoptotic NOXA increased during trot merit.
In conclusion, dasatinib/fludarabine combination has modest clinical efficacy in fludarabine-refractory patients. (C) 2013 Elsevier Ltd, All rights reserved.
- Hudarabine refractory
- Kinase inhibitor
- KINASE INHIBITOR DASATINIB
- B-CELL RECEPTOR
- NOXA/MCL-1 BALANCE
- RESPONSE CRITERIA
- TYROSINE KINASE
- SALVAGE THERAPY