Phase Ib trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma

Christian Grommes, Sarah S. Tang, Julia Wolfe, Thomas J. Kaley, Mariza Daras, Elena I. Pentsova, Anna F. Piotrowski, Jacqueline Stone, Andrew Lin, Craig P. Nolan, Malbora Manne, Paolo Codega, Carl Campos, Agnes Viale, Alissa A. Thomas, Micheal F. Berger, Vaios Hatzoglou, Anne S. Reiner, Katherine S. Panageas, Lisa M. DeAngelis and Ingo K. Mellinghoff

Key points

  • Ibrutinib/methotrexate/rituximab combination treatment is safe and shows promising clinical activity in CNS lymphoma.

  • Circulating tumor DNA analysis of cerebrospinal fluid may be useful to monitor disease burden in patients with CNS lymphoma.


Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory (r/r) central nervous system lymphoma (CNSL). Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a Phase Ib clinical trial to explore the sequential combination of ibrutinib at 560 or 840 mg daily dosing with methotrexate (HD-MTX) and rituximab in patients with CNSL. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses (4 cycles; cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX-clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX and rituximab was tolerated with acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. 11/15 patients proceeded to maintenance ibrutinib after completing four cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12/15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. The study is registered to as NCT02315326.

  • Submitted September 19, 2018.
  • Accepted December 15, 2018.