Disease Overview

PCNSL is a form of non-Hodgkin lymphoma that originates within the central nervous system (CNS), including the brain, spinal cord, and eyes. Unlike other lymphomas that primarily involve lymph nodes, PCNSL is confined to the CNS.

Epidemiology

PCNSL is most commonly diagnosed in older adults, particularly those over the age of 60, with a median age at diagnosis around 60 years old. It occurs more frequently in individuals with compromised immune systems, such as those with HIV/AIDS or who have undergone organ transplantation. PCNSL accounts for approximately 1% of all non-Hodgkin lymphomas and between 3% to 4% of all primary brain tumors. The annual incidence worldwide is around 0.4 cases per 100,000 individuals. Although rare, its incidence has been slightly increasing in recent years.

Diagnostic Criteria 

Diagnosis of PCNSL involves imaging studies such as magnetic resonance imaging (MRI) with contrast, which helps identify characteristic brain lesions. Definitive diagnosis requires biopsy of brain tissue or cerebrospinal fluid to analyze for lymphoma cells. Guidelines from organizations like the National Comprehensive Cancer Network (NCCN) outline the diagnostic approach.

Clinical Presentation

Patients with PCNSL often present with neurological symptoms, including focal deficits such as weakness or sensory loss, cognitive impairment, seizures, and headaches. Visual disturbances may occur if the eyes are involved. Symptoms typically progress rapidly over weeks to months.

Evaluation / Diagnosis  

Diagnostic evaluation includes thorough imaging of the brain and sometimes the eyes to assess the extent and location of tumors. Biopsy of affected tissues is critical for confirming the presence of lymphoma cells and distinguishing PCNSL from other brain tumors or inflammatory conditions.

Management

Treatment of PCNSL primarily involves chemotherapy, most commonly high-dose methotrexate (HD-MTX), which is effective in crossing the blood-brain barrier to target cancer cells within the CNS. Additional therapies may include radiation therapy, especially in cases of recurrence or for localized disease. Surgery is generally not considered standard due to the multifocal and deep-seated nature of PCNSL tumors.

One promising avenue is Tirabrutinib (ONO-4059), an oral therapy that targets Bruton tyrosine kinase (BTK), crucial for the survival and proliferation of B-cell cancers. Tirabrutinib has received approvals in Japan, South Korea, and Taiwan for relapsed or refractory PCNSL, demonstrating its efficacy in inhibiting abnormal B-cell receptor signaling. Recently granted Orphan Drug designation by the FDA in 2023, Tirabrutinib is now undergoing phase 2 trials (PROSPECT) to further evaluate its safety and efficacy in treating PCNSL.

Another innovative therapy, Orelabrutinib (ICP-022), a second-generation BTK inhibitor with enhanced brain penetration, has shown promise in various lymphomas, including PCNSL. Studies combining Orelabrutinib with PD-1 inhibitors have reported rapid responses in patients with relapsed and refractory PCNSL. Phase 2 clinical trials are currently ongoing to assess its effectiveness in broader patient populations.

PI3K/mTOR inhibitors like Paxalisib (GDC-0084) are also under investigation for their potential to disrupt the PI3K/mTOR pathway, critical for cancer cell growth and survival. Paxalisib has shown encouraging early results in treating recurrent or refractory PCNSL and holds multiple designations for other cancers affecting the central nervous system.

Innovative approaches such as CAR T-cell therapy and GNC-038, a novel tetra-specific antibody, are also being explored. CAR T-cell therapies, despite concerns over neurotoxicity, are being studied in clinical trials targeting CD19-expressing cells. GNC-038, meanwhile, aims to engage T cells against CD19 or PD-L1-overexpressing tumor cells in PCNSL, showing early potential in phase 1/2 trials.

Overall, these experimental therapies represent a critical frontier in PCNSL treatment, offering hope for improved outcomes and survival rates among patients facing this challenging disease. Continued research and clinical trials will be essential to further refine these therapies and expand treatment options for PCNSL.