Interim results of a phase I trial of intraventricular rituximab plus methotrexate in recurrent CNS lymphoma: Macrophage polarization and acquired resistance to therapy.

Abstract

2532 Background: We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS lymphomas (JCO 2007 25: 1350-1356). While most patients exhibited initial responses to rituximab, acquired resistance usually developed, most often within 2 to 12 weeks. While rituximab efficacy appears to be mediated predominantly by ADCC, with tumor-associated macrophages being the dominant effector cell, there is an extreme paucity of data regarding the role and phenotype of macrophages in NHL. We hypothesize that the phenotype of intratumoral macrophages (M1 vs. M2) may be a determinant of rituximab efficacy and resistance. Methods: Thus far, six patients with recurrent CD20+ CNS NHL have been treated at UCSF on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned eleven week schedule. Rituximab is combined with MTX (12 mg) during the second intrathecal injection each week. We implemented a novel flow-cytometry-based method, developed in our laboratory, to serially isolate and characterize distinct subpopulations of tumor macrophages from CSF, based upon the relative expression of nitric oxide synthase (iNOS) and CD206. Results: No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. While there is preliminary evidence for efficacy using this combination, with the most durable response being eight months, resistance developed in each of the patients thus far treated. Notably, we detected increases in the proportion of CSF M2 macrophages compared to baseline (usually greater than 3-fold; p<0.001) which anticipated the onset of rituximab resistance and tumor progression in each of these cases. Conclusions: Intraventricular rituximab/MTX is potentially safe and active in recurrent CNS NHL. The elucidation of distinct subpopulations of lymphoma macrophages may provide insight into tumor pathogenesis, prognosis, and rituximab resistance. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. No significant financial relationships to disclose.