Can Camptothecin-11 Analog Improve Response to Fludarabine in CLL?
Posted: Monday, August 10, 2020
According to research published in Open Biology, the camptothecin-11 analog EZN-2208 may interrupt protective microenvironmental interactions that promote disease progression in patients being treated with fludarabine for chronic lymphocytic leukemia (CLL). EZN-2208 has previously been shown to inhibit HIF-1α, a transcription factor overexpressed in this patient population.
“Surprisingly, we observed that although EZN-2208 added therapeutic value to fludarabine treatment in vitro, in co-cultures where CLL cells are protected from cell death by [bone marrow]-derived stromal cells...in the more complex in vivo microenvironment, EZN-2208 sensitized CLL cells to fludarabine only partially,” noted Rosa Bernardi, PhD, of the IRCCS San Raffaele Scientific Institute in Milan, and colleagues.
A slow-progressing model of Eμ-TCL1–derived CLL was transplanted into mice for the in vitro trial. The mice underwent the first round of treatment 34 days after transplantation of leukemic cells, receiving 5 mg/kg–1 of EZN-2208, 34 mg/kg–1 of fludarabine, or a combination of both. After 43 days, at the end of the first cycle, a significant reduction in the leukemia burden in the spleen and the bone marrow was noted for the combination treatment alone. The remaining mice underwent a second treatment cycle. On day 63, the second cohort was found to have a substantially lower disease burden in those treated with EZN-2208 monotherapy or combination treatment.
An in vivo trial included the transplantation of the human CLL cell line MEC-1 into a mouse model that is not sensitive to fludarabine. A total of 5 mg/kg–1 of EZN-2208 was administered. This treatment was found to slow disease progression. Upon the addition of fludarabine, no additive effects were noted. However, a combination treatment of EZN-2208 and fludarabine did reduce disease involvement in the bone marrow.
Disclosure: The study authors reported no conflicts of interest.
