CSF ctDNA Clearance Correlates with Sustained Response in CNS Lymphoma Combination Therapy Trial
In this phase 1b trial, the combination of ibrutinib, high-dose methotrexate and rituximab achieved clinical responses in 80% of patients with recurrent/refractory CNS lymphoma with an acceptable safety profile. Next-generation sequencing of ctDNA in cerebrospinal fluid demonstrated that sustained tumour responses were associated with CSF ctDNA clearance, validating liquid biopsy monitoring in a compartment where tissue biopsy is particularly challenging.
The original study
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.
- Authors
- Grommes C, Tang SS, Wolfe J, Kaley TJ, Daras M, Pentsova EI, et al.
- Journal
- Blood
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- PMID
- 30567753
Original 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 = 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.