Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma with an annual estimated incidence of 0.48 per 100,000 person-years.1 It accounts for approximately 3% of all CNS tumors and develops within the brain, spinal cord, eye, or leptomeninges.2

According to the National Comprehensive Cancer Network, systemic therapy with high-dose methotrexate is the most effective agent to treat primary brain lymphoma, and it is commonly used in combination with drugs such as vincristine, procarbazine, cytarabine, rituximab, or ifosfamide.2 Induction chemotherapy is typically followed by consolidation whole-brain radiation therapy to maximize response and improve outcomes.2 Treatment options that include nonmyeloablative chemotherapy and high-dose chemotherapy along with stem cell transplantation are based on center expertise and patient eligibility.3 Currently, no targeted or immunotherapeutic agents are approved for the treatment of PCNSL.

A review published in Blood highlights new approaches that are being investigated to treat PCNSL based on the mutational landscape and signaling pathways that are extant in the disease.3

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Bruton Tyrosine Kinase Inhibition in PCNSL

Targeting Bruton tyrosine kinase (BTK) with ibrutinib is supported by insights into its biology, especially regarding B-cell receptor signaling dependency, the authors reasoned. They observed that most studies with this drug were not comparative, with meaningful responses for lymphoma regression observed in 50% of patients and overall response rates of 77% observed in patients with relapsed/refractory (r/r) PCNSL.

The review summarized findings from the French LYSARC group, which conducted a multicenter, single-arm study in 52 patients with r/r PCNSL. An interim analysis reported complete responses (CR) in 10 (19%) patients and partial responses (PR) in 16 (31%) patients. In this study, 32 of 52 patients (62%) stopped treatment, mainly due to disease progression. In addition to the known toxicities of ibrutinib, two cases of pulmonary Aspergillus infection (one being fatal) were also reported.3

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Another study highlighted was a nonrandomized, single center, dose-escalation study of single-agent ibrutinib in r/r PCNSL (13 patients) and secondary CNS lymphoma (7 patients). In the PCNSL cohort, the objective response rate was 77% (CR: 5; PR: 5). The study reported a median progression-free survival (PFS) of 4.6 months and a median overall survival (OS) of 15 months.5

The review noted that responses seen in PCNSL with ibrutinib were higher than those seen outside the CNS in r/r diffuse large B-cell lymphomas. But the nondurable remissions and the incidence of Aspergillus infection with ibrutinib in PCNSL require further investigation.3

Noting that a protocol that combined ibrutinib with immune poly-chemotherapy called DA-TEDDI-R (temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab, and intrathecal cytarabine) was associated with a high 17% treatment-related mortality in a relatively young cohort of patients, it was suggested that investigating combinations of ibrutinib should be restricted to chemotherapy agents that have shown efficacy and safety in this setting.6