Therapy of Refractory (Recurrent) CNS Leukemia by Concentration × Time Methotrexate

Abstract

We have treated three patients with ALL in recurrent and refractory CNS relapse with intraventricular methotrexate (MTX) via an Ommaya reservoir by a low-dose “concentration × time” schedule of 1 mg every 12 hr for 3 days. This method was originally devised by Bleyer et al to maintain minimal cytocidal MTX concentration in CSF for the entire cell cycle time while eliminating the high peak level responsible for neurotoxicity. In spite of the fact that all the patients had been in relapse after repeated intrathecal MTX (12 mg/m²) and/or high dose MTX with abnormal radiological imaging (n=2), neurological deficits (n=2) and/or acute MTX toxicity (n=2), remission was achieved in each patient without neurotoxicity. We have studied the concentration of intraventricular MTX in a total of 60 samples and confirmed that CSF concentration of MTX was maintained at greater than 1 μM in 47 of 60 (78%) injections. Our data suggest that the “C × T” MTX via an Ommaya reservoir is an effective and safe treatment for patients with CNS leukemia.