Phase II of Single-Agent Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in various B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL.

METHODS: 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, systemic disease needed to be absent. All patients needed to have at least one prior CNS directed therapy.

RESULTS: Forty-four patients were enrolled; 3 received ibrutinib at 560mg and 41 at 840mg. Median age was 68 years (range 21-90); 20 were women. Median ECOG was 1 (0: 11, 1: 22, 2: 11); 29 had PCNSL and 15 SCNSL; 61% had recurrent disease. Twenty-four had isolated parenchymal disease, 4 isolated cerebrospinal fluid (CSF) involvement and 16 both. No grade 5 event has been observed. Eleven patients experienced 12 grade 4 adverse events: neutropenia (in 5 patients), lymphopenia (2), ALT elevation (1), combined ALT/AST elevation (1), sepsis (1), and pneumonitis (1). Seventeen patients experienced 35 grade 3 adverse events (most common: lymphopenia in 4, ALT elevation (3), hyperglycemia (3), urinary tract infection (3), decreased WBC (2), lung infection (2), and thrombocytopenia (2)). Treatment was stopped due to adverse events in 3 patients (grade 4 pulmonitis, grade 4 liver toxicity, grade 3 infectious encephalitis). Twenty-four patients did not experience ≥3 grade adverse events. The most common toxicities at any grade were thrombocytopenia (73%), hyperglycemia (55%), anemia (43%), hypercholesterolemia (43%) and hypertriglyceridemia (43%) of which most were grade 1/2. Only 1 Aspergillus infection has been observed in a patient with chronic steroid use. After a median follow-up of 22 months (range 1.5-39), 40/44 patients were evaluated for response (4 did not complete at least 15 days of drug treatment due to deteriorating clinical status or withdrawal from study). Overall response was 78% (31/40; 81% (22/27) in PCNSL; 69% (9/13) in SCNSL) with 17 CR, 14 PR, 4 SD and 5 PD as best response. The median PFS is 4 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 16.5 months). The median overall survival is 19.5 months.

CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 78% of CNS lymphoma patients.