BTK Inhibitor–Based Combinations May Improve the Efficacy of SOC Treatment in CNS Lymphoma

Avyakta Kallam, MBBS

Methotrexate continues to prevail as the standard of care (SOC) in patients with primary central nervous system (CNS) lymphoma, although novel treatments with BTK inhibitors, such as ibrutinib (Imbruvica), may rise to resolve still-unmet needs, according to Avyakta Kallam, MBBS.

Chemotherapy regimens with high-dose methotrexate can help 65%-80% of patients achieve tumor regression, Kallam shared in a presentation at the 2022 Pan Pacific Lymphoma Conference.¹ However, 50% of these patients may recur on this therapy. Consolidation maintenance strategies with agents such as BTK and PI3K inhibitors may reduce the risk of recurrence in fit patients.

“Targeted agents are under investigation, and they appear to be promising,” Kallam said. “However, they haven’t quite made their way into frontline treatment as of yet.”

In an interview with OncLive^®, Kallam, an assistant professor in the Department of Internal Medicine, Division of Oncology & Hematology at the University of Nebraska Medical Center, discussed the benefits and shortcomings of the current SOC in CNS lymphoma and expressed the importance of studying frontline targeted agents in this population.

OncLive^®: Could you provide a general overview of your presentation and pull out some of the main points you relayed?

Kallam: My talk was focused on frontline treatment for primary CNS lymphoma. Primary CNS lymphoma is 1 of the less common types of non-Hodgkin lymphomas and has a poor prognosis. [Since this disease has poorer outcomes,] it’s important to strategize how to best treat it. My presentation was primarily centered around frontline treatments, namely chemotherapy, and the role of consolidation strategies in this disease.

What is the SOC in patients with primary CNS lymphoma in the frontline setting, and how do induction and consolidation therapies factor into these treatment decisions?

The current SOC in patients with primary CNS lymphomas is chemotherapy, which incorporates high-dose methotrexate. We have several frontline combination chemotherapy regimens, which all incorporate methotrexate. That forms the mainstay of treatment.

As a second step, following up to treatment in the frontline setting, we use consolidation strategies to decrease the risk of relapse. The most commonly used consolidation strategy is high-dose chemotherapy, followed by an autologous stem cell transplant [ASCT].

Given that patients with primary CNS lymphoma do have such a poor prognosis, what unmet needs still need to be addressed to potentially improve some of these outcomes?

One of the biggest challenges we face in patients with primary CNS lymphoma is the location of the tumor, because the blood-brain barrier prevents entry of several chemotherapy drugs that we [would] typically use in other types of systemic lymphomas. We’re limited by the choices of agents that we can give in this disease.

The second challenge is that typically these patients are older and have multiple comorbid conditions, which makes it difficult for them to tolerate some of the treatments.

What role could targeted agents such as PI3K inhibitors or BTK inhibitors potentially play in these patients?

BTK inhibitors, particularly ibrutinib, have the ability to penetrate the blood-brain barrier. [Because of their] mechanism of their action, they can cause increased cell death and apoptosis, so they’re being increasingly used in this disease. However, they haven’t quite made their way into frontline regiments yet. They are being explored as a second-line regimen, and, similarly to PI3K inhibitors, research and development with these agents is fairly early in that setting. In terms of novel agents, 1 of the most commonly used novel agents in this disease is ibrutinib.

What ongoing clinical trials are you intrigued by that could potentially move some of these agents to the frontline setting?

There is a phase 1/2 study [NCT02315326] that seems exciting. It’s incorporating ibrutinib in the frontline setting, using a combination of methotrexate, ibrutinib and procarbazine. Another [phase 2] study [NCT04934579] is looking at a combination of methotrexate, lenalidomide [Revlimid], and rituximab [Rituxan] in the frontline setting. These 2 studies appear promising.

What main message from your presentation would you like to impart to colleagues?

Methotrexate-based, multi-agent chemotherapies continue to remain the standard frontline treatment in [CNS lymphoma]. Once a patient is diagnosed with primary CNS lymphoma, it is important to evaluate their [ECOG] performance status to see if they would be eligible to receive methotrexate. If they are, I would strongly recommend going ahead with the methotrexate-based chemotherapy regimen, followed by consolidation therapy with ASCT.

What else is important to know about the evolution of CNS lymphoma treatment?

One thing that will be important in this disease is the development of biomarkers down the road, which will help us in determining outcomes and predicting which patients will respond to methotrexate.

Reference

1. Kallam A. Primary central nervous system (CNS) lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI. https://bit.ly/3IUBkUQ