Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study

Arnon P. Kater, Marjolein Spiering, Roberto D. Liu, G. Doreen te Raa, E. Slinger, Sanne H. Tonino, Marielle M. Beckers, Simon Daenen, Jeanette K. Doorduijn, Nienke A. G. Lankheet, Dieuwertje M. Luijks, Eric Eldering, Marinus H. J. van Oers

Research output: Contribution to journalArticle*Academicpeer-review

Abstract

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 (100mg/day, days 1-28) followed by combination of dasatinib with fludarabine (40mg/m²/day, days 1-3 every 28 day) for a total of 6 cycles in fludarabine-refractory CLL. 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% finished at least 2 cycles of combination treatment. 3 of these 18 patients reached a formal PR (16.7%). Majority of patients obtained some reduction in lymph node (LN) size. Most frequent toxicity was related to myelosuppression. NF-κB RNA expression levels of circulating CLL cells decreased whereas the levels of pro-apoptotic NOXA increased during treatment. In conclusion, dasatinib/fludarabine combination has modest clinical efficacy in fludarabine-refractory patients
Original languageEnglish
Pages (from-to)34-41
JournalLeukemia Research
Volume38
Issue number1
DOIs
Publication statusPublished - 2014

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