Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma Academic Article uri icon


MeSH Major

  • Astrocytoma
  • Brain Neoplasms
  • Chromosome Deletion
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 19
  • Oligodendroglioma


  • © 2019 by The American Society of Hematology. 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 5 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.

publication date

  • January 31, 2019



  • Academic Article



  • eng

PubMed Central ID

  • PMC6356986

Digital Object Identifier (DOI)

  • 10.1182/blood-2018-09-875732

PubMed ID

  • 30567753

Additional Document Info

start page

  • 436

end page

  • 445


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