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


Authors: Grommes, C.; Tang, S. S.; Wolfe, J.; Kaley, T. J.; Daras, M.; Pentsova, E. I.; Piotrowski, A. F.; Stone, J.; Lin, A.; Nolan, C. P.; Manne, M.; Codega, P.; Campos, C.; Viale, A.; Thomas, A. A.; Berger, M. F.; Hatzoglou, V.; Reiner, A. S.; Panageas, K. S.; DeAngelis, L. M.; Mellinghoff, I. K.
Article Title: Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma
Abstract: 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 www.clinicaltrials.gov as #NCT02315326. © 2019 by The American Society of Hematology.
Journal Title: Blood
Volume: 133
Issue: 5
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2019-01-31
Start Page: 436
End Page: 445
Language: English
DOI: 10.1182/blood-2018-09-875732
PUBMED: 30567753
PROVIDER: scopus
PMCID: PMC6356986
DOI/URL:
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Anne S Reiner
    120 Reiner
  2. Thomas Kaley
    82 Kaley
  3. Christian Grommes
    52 Grommes
  4. Katherine S Panageas
    327 Panageas
  5. Craig Nolan
    42 Nolan
  6. Michael Forman Berger
    380 Berger
  7. Carl Campos
    22 Campos
  8. Mariza Daras
    15 Daras
  9. Alissa A Thomas
    15 Thomas
  10. Jacqueline Blair Stone
    9 Stone
  11. Andrew Lee Lin
    9 Lin
  12. Paolo Codega
    6 Codega
  13. Julia Catherine Wolfe
    8 Wolfe
  14. Sarah Shiann Tang
    3 Tang
  15. Malbora Manne
    3 Manne