Related Experiment Video
Updated: May 5, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter
Arnon P Kater1, Marjolein Spiering2, Roberto D Liu2
1Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands; LYMMCARE (Lymphoma and Myeloma Center Amsterdam), The Netherlands.
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.
Insights
This study investigated the combination of dasatinib and fludarabine for fludarabine-refractory chronic lymphocytic leukemia (CLL). The treatment showed modest clinical efficacy, with some patients achieving partial response and lymph node size reduction.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Chronic lymphocytic leukemia (CLL) resistance to chemotherapy is linked to antiapoptotic protein overexpression driven by microenvironmental signals.
- Dasatinib demonstrates in vitro efficacy by inhibiting these proteins and restoring fludarabine sensitivity in activated CLL cells.
Purpose of the Study:
- To evaluate the clinical efficacy of a sequential dasatinib monotherapy followed by a dasatinib-fludarabine combination regimen.
- To assess the treatment in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL).
Main Methods:
- A total of 20 patients with fludarabine-refractory CLL were enrolled.
- Treatment involved one cycle of dasatinib monotherapy (100mg/day) followed by 6 cycles of dasatinib combined with fludarabine (40mg/m²/day).
- The primary endpoint was the overall response rate using IWCLL'08 criteria.
Main Results:
- Of 18 patients completing at least one cycle, 16.7% achieved a partial response (PR).
- Most patients experienced a reduction in lymph node size.
- The most common toxicity observed was myelosuppression.
- NF-κB RNA expression decreased, while pro-apoptotic NOXA increased in circulating CLL cells.
Conclusions:
- The combination of dasatinib and fludarabine exhibits modest clinical efficacy in fludarabine-refractory CLL patients.
- The observed molecular changes suggest a potential mechanism of action involving modulation of apoptotic pathways.
