A phase II study assessing long-term response to ibrutinib monotherapy in recurrent or refractory CNS lymphoma Journal Article
| Authors: | Grommes, C.; Nandakumar, S.; Schaff, L. R.; Gavrilovic, I.; Kaley, T. J.; Nolan, C. P.; Stone, J.; Thomas, A. A.; Tang, S. S.; Wolfe, J.; Bozza, A.; Wongchai, V.; Hyde, A.; Barrett, E.; Lynch, E. A.; Madzsar, J. T.; Lin, A.; Piotrowski, A. F.; Pentsova, E.; Francis, J. H.; Hatzoglou, V.; Schultz, N.; Reiner, A. S.; Panageas, K. S.; DeAngelis, L. M.; Mellinghoff, I. K. |
| Article Title: | A phase II study assessing long-term response to ibrutinib monotherapy in recurrent or refractory CNS lymphoma |
| Abstract: | PURPOSE: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up. ©2024 American Association for Cancer Research. |
| Keywords: | adult; treatment outcome; aged; aged, 80 and over; middle aged; genetics; mutation; clinical trial; mortality; phase 2 clinical trial; neoplasm recurrence, local; protein kinase inhibitor; drug resistance; pathology; drug resistance, neoplasm; pyrimidines; central nervous system tumor; central nervous system neoplasms; protein kinase inhibitors; pyrazole derivative; tumor recurrence; pyrazoles; lymphoma; piperidines; drug therapy; pyrimidine derivative; adenine; piperidine derivative; bruton tyrosine kinase; ibrutinib; very elderly; humans; human; male; female; agammaglobulinaemia tyrosine kinase |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 18 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-09-15 |
| Start Page: | 4005 |
| End Page: | 4015 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-0605 |
| PUBMED: | 38995739 |
| PROVIDER: | scopus |
| PMCID: | PMC11398981 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Christian Grommes -- Source: Scopus |
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