Development of chemoresistance in chronic lymphocytic leukemia (CLL) is at least partly mediated by protective stimuli within the lymph node (LN) microenvironment. Dasatinib has activity against multiple kinases which have been reported to be activated by the microenvironment, including SRC, c-Abl and BTK. We have recently shown that Dasatinib can effectively inhibit the anti-apoptotic program and as a consequence, restore fludarabine sensitivity in vitro.
We conducted an open-label phase 2 trial of Dasatinib combined with fludarabine in twenty refractory CLL patients. Patients were treated with Dasatinib 100 mg once daily for 28 days. In patients who did not reach at least a PR, fludarabine was added (40 mg/m2 for 3 consecutive days q28) for at least 2 and a maximum of 6 cycles. Response assessments included CT-scans at baseline, following 4 weeks of Dasatinib monotherapy, after 2 cycles of combination therapy and at the end of protocol. In a subset of patients with high numbers of circulating lymphocytes at baseline, RNA expression profiles of apoptosis regulator genes as well as inflammation genes were analyzed prior and during treatment by MLPA analysis.
Toxicities were comparable to those observed in fludarabine containing regimens and as expected in heavily pre-treated refractory patients.
Three patients (18%) reached a PR. Although most patients did not reach a formal nodal response, most patients showed reduction in lymph node (LN) size with a median of −20% as best response. Subsequent dasatinib fludarabine treatment following dasatinib monotherapy induced additional clinical effects but primarily in patients without del11q or del17p. Patients with a LN reduction of at least 20% had a significant improved PFS (256 days) and OS (510 days) as compared to non-responders (80 days and 158 days respectively). Also, in responding patients PFS was superior to PFS after last prior treatment.
NF-κB expression levels decreased while expression levels of the pro-apoptotic gene NOXA increased both after Dasatinib treatment and combination treatment.
In conclusion, Dasatinib fludarabine combination treatment has clinical efficacy in heavily pretreated refractory patients which correlated with decreased NF-κB and increased NOXA expression. As recently showed with other targeted agents, improvement of PFS and OS is also observed in patients with tumor responses less than 50%. These data do encourage further studies on a broad-spectrum kinase inhibitor like Dasatinib in combination with other classes of drugs in relapsed and refractory CLL.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.