Mark Roschewski, a clinical investigator at the National Cancer Institute in Bethesda, Maryland, shared his research findings at the 2023 American Society of Hematology (ASH) conference, offering hope for patients with aggressive DLBCL affecting the central nervous system (brain and spinal cord).

What are BTK Inhibitors?

The BTK gene guides the creation of a protein called Bruton tyrosine kinase (BTK). This protein is vital for the growth and maturity of B cells, special white blood cells that defend the body from infections. However, when this system malfunctions, the B cells can start multiplying uncontrollably, causing lymphoma.  

BTK inhibitors do their job by disrupting the B cell's communication system. The inhibitors stop this communication, preventing the abnormal B cells from growing. Instead, these troublesome cells end up dying off.

Ibrutinib is a well-known BTK inhibitor. What differentiates this medication from other BTK inhibitors is its ability to penetrate the blood-brain barrier. This pathway typically does not allow drugs to pass into the central nervous system.

Central Nervous System DLBCL

Lymphoma involving the central nervous system occurs most often in diffuse large B-cell lymphoma and other fast-growing non-Hodgkin lymphomas.

There are two types of CNS lymphoma: primary and secondary. Primary CNS lymphoma occurs when the lymphoma starts in the central nervous system. Secondary CNS lymphoma occurs when the cancer starts somewhere else in the body and spreads to the central nervous system. 

This population has a historically poor prognosis due to the limited effectiveness of chemotherapy in crossing the blood-brain barrier. Lymphoma cells can survive within this body system even when all other cancer has been killed off. This challenge can cause patients not to achieve remission, or to relapse after treatment.

Combined Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Ibrutinib, and Rituximab (TEDDi-R) for CNS DLBCL

The research team at the National Cancer Institute leveraged the known ability of ibrutinib to cross the blood-brain barrier and combined it with chemotherapy, creating the TEDDi-R regimen. This combination includes temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab.

Between 2019 and 2023, 50 patients were enrolled in the TEDDi-R study with a median age of 63. Most were male patients with relapsed (returning disease) or refractory (not responding) DLBCL.

Preliminary TEDDi-R Clinical Trial Results

The primary goal was to assess the efficacy of this combination in achieving complete responses, particularly lasting ones. 

The current results of the phase two study are nothing short of remarkable. Even patients as old as 89 can tolerate the treatment, marking a crucial achievement in expanding therapeutic options for a population with limited choices. The treatment regimen demonstrated a complete response rate of 71%.

The study revealed a substantial number of patients who maintained remission for extended periods of time – up to four years. This prolonged remission suggests the potential to not only provide an alternative for patients who have exhausted standard therapy but also to offer hope of curing their lymphoma, even when the central nervous system is involved.

TEDDi-R Open Enrollment

Mark Roschewski's presentation signifies a significant step forward in addressing the complexities of aggressive DLBCL entailing the central nervous system. The innovative combination of ibrutinib and chemotherapy in TEDDi-R emerges as a promising option, providing renewed hope and potential cures for patients who have navigated the limitations of standard therapies.

The TEDDi-R study is still recruiting patients who meet the inclusion and exclusion criteria.