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Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

  • Grommes, Christian1, 2, 3
  • Tang, Sarah S2
  • Wolfe, Julia1
  • Kaley, Thomas J1, 3
  • Daras, Mariza1, 3
  • Pentsova, Elena I1, 3
  • Piotrowski, Anna F1, 3
  • Stone, Jacqueline1, 3
  • Lin, Andrew1, 3
  • Nolan, Craig P1, 3
  • Manne, Malbora1
  • Codega, Paolo2
  • Campos, Carl2
  • Viale, Agnes4
  • Thomas, Alissa A1
  • Berger, Michael F4, 5, 6
  • Hatzoglou, Vaios7
  • Reiner, Anne S8
  • Panageas, Katherine S8
  • DeAngelis, Lisa M1, 3
  • And 1 more
  • 1 Department of Neurology and.
  • 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 3 Department of Neurology, Weill Cornell Medical College, New York, NY.
  • 4 Marie-Josée and Henry R. Kravis Center for Molecular Oncology and.
  • 5 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 6 Department of Pathology, Weill Cornell Medical College, New York, NY.
  • 7 Department of Radiology and.
  • 8 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; and.
  • 9 Department of Pharmacology, Weill Cornell Medical College, New York, NY.
Published Article
American Society of Hematology
Publication Date
Jan 31, 2019
DOI: 10.1182/blood-2018-09-875732
PMID: 30567753


Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 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 an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at as #NCT02315326. © 2019 by The American Society of Hematology.

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