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
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work