1. A Phase II Study Assessing Long-term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma.
- Author
-
Grommes C, Nandakumar S, Schaff LR, Gavrilovic I, Kaley TJ, Nolan CP, Stone J, Thomas AA, Tang SS, Wolfe J, Bozza A, Wongchai V, Hyde A, Barrett E, Lynch EA, Madzsar JT, Lin A, Piotrowski AF, Pentsova E, Francis JH, Hatzoglou V, Schultz N, Reiner AS, Panageas KS, DeAngelis LM, and Mellinghoff IK
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Drug Resistance, Neoplasm, Lymphoma drug therapy, Lymphoma mortality, Lymphoma pathology, Pyrazoles therapeutic use, Pyrazoles administration & dosage, Pyrazoles adverse effects, Pyrimidines therapeutic use, Pyrimidines administration & dosage, Pyrimidines adverse effects, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors administration & dosage, Treatment Outcome, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Agammaglobulinaemia Tyrosine Kinase genetics, Mutation, Adenine analogs & derivatives, Adenine therapeutic use, Piperidines therapeutic use, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms secondary, Central Nervous System Neoplasms mortality, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology
- 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.)
- Published
- 2024
- Full Text
- View/download PDF