PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a progression free survival (PFS) of 2-5 months. Ibrutinib has shown promising clinical response in some B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL.
Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, ECOG ≤ 2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent.
Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. The median prior CNS directed therapy was 2; all methotrexate regimens. Despite clinical and radiographic response, 2 patients withdrew and 1 stopped due to toxicity (fungal infection). Four grade 4 toxicities were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (1)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 147 days, 16/20 patients were evaluated for response: 4 CR (3 in CSF; 1 in the parenchyma), 9 PR, and 3 PD; 65% (13/20) ORR. In 3 patients response has not been confirmed in a 2nd assessment. The median PFS is 5.5 months (longest: 13.2 months). The mean Ibrutinib concentration in the CSF at day 1 and 29 was 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM). The CSF Ibrutinib concentrations reached in patients is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells. Molecular testing is in process to associate genomic alterations and outcome.
Patients with CNS lymphoma tolerate Ibrutinib with manageable toxicities. Ibrutinib might be a therapeutic alternative that should be further investigated in r/r CNS lymphoma patients.
Clinical trial identification
Legal entity responsible for the study
Memorial Sloan Kettering Cancer Center
All authors have declared no conflicts of interest.
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