Most CML patients who have a suboptimal response to imatinib have low OCT-1 Activity. Higher doses of imatinib may overcome the negative impact of low OCT-1 Activity.
The group of T. Hughes in Adelaide provides interesting data on the role of the drug transporter OCT-1. Its activity is an important determinant of molecular response to Imatinib. The authors claim that pre-therapy determination of OCT-1 activity identifies patients at highest risk for achieving a suboptimal response (in these patients dose intensity is critical), and those likely to respond well to standard dose imatinib.
Blood. 2007 Aug 30; [Epub ahead of print]
FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia.
Transformation to blast crisis in CML is associated with protein phosphatase 2A (PP2A) expression. The immunosuppressant FTY720, which is currently tested in clinical trials in organ transplantation and autoimmune diseases, is known to activate PP2A. The authors demonstrate remarkable anti-tumoral activity in vitro and in pre-clinical animal models of FTY720 against bcr-abl cell lines (including T315I positive cell lines) and primary cells from CML blast crisis and Ph+ ALL. The presented data strongly support the clinical testing of the PP2A activator FTY720 in the treatment of CML-BC and Ph1+ ALL patients.
J Clin Invest. 2007 Aug 23; [Epub ahead of print]
How I treat chronic myeloid leukemia in the imatinib era.
This concise review summarizes recently published data on CML management with respect to their implication for clinical decision making.
Goldman JM Blood. 2007 Jul 12; [Epub ahead of print].
The immunogenicity of Bcr-Abl expressing dendritic cells is dependent on the Bcr-Abl kinase activity and dominated by Bcr-Abl regulated antigens.
Scheich and co-workers provide valuable information on the immunogenicity of Bcr-Abl positive leukemia. Interestingly, it appears that not the neo-epitopes represented by the novel fusion protein induce relevant HLA class I restricted T cell responses, but that Bcr-Abl regulated antigens potently stimulate peptide-specific CTL responses. In line with this in vitro data, the T cell repertoire of a patient with CML in major molecular remission under Imatinib therapy was dominated by T cells directed against Bcr-Abl regulated antigens. Their data strengthen efforts to develop immunotherapeutical approaches targeting Bcr-Abl regulated antigens for the treatment of CML patients with residual disease under therapy with TK inhibitors.
Scheich F, Duyster J, Peschel C, Bernhard H. Blood. 2007 Jun 19; [Epub ahead of print].