Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with Imatinib (STI-571)

Isolated central nervous system ( CNS) relapse occurred in 5 out of 24 patients ( 20.8%) with chronic myeloid leukemia ( CML) lymphoid blast crisis ( 2), Philadelphia ( Ph) chromosome positive acute lymphoblastic leukemia ( ALL) ( 2) or CML with biphenotypic markers ( 1) treated on imatinib mesylate ( IM) protocols at our institution. CNS relapse occurred despite peripheral blood ( 5) and bone marrow ( 3) complete responses. Median time to CNS relapse was day 32 ( range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid ( CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma ( 0.044 mug/ ml ( 0.088 +/- 0.029 muM) vs 3.27 mug/ ml ( 6.54 +/- 0.93 muM)). CSF levels were substantially below the concentration required for inhibition of BCR- ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/ brain barrier and its implications are discussed.