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Preclinical and clinical evaluation of Buparlisib (BKM120) in recurrent/refractory Central Nervous System Lymphoma
Christian Grommes1,2,3, Elena Pentsova1,3, Lauren R Schaff1,3
1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited treatment options. Targeting the phosphoinositide 3-kinase (PI3K) pathway yields promising responses across B-cell malignancies, but its therapeutic potential in CNS lymphomas remains unexplored. We present pre-clinical and clinical data on the pan-PI3K inhibitor Buparlisib in CNS lymphomas. In a primary CNS lymphoma-patient-derived cell line, we define the EC50. Four patients with recurrent CNS lymphoma were enrolled in a prospective trial. We evaluated Buparlisib plasma and cerebrospinal fluid pharmacokinetics, clinical outcomes, and adverse events. Treatment was well tolerated. Common toxicities include hyperglycemia, thrombocytopenia, and lymphopenia. The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364.
Insights
The pan-PI3K inhibitor Buparlisib showed poor efficacy in central nervous system (CNS) lymphomas, with low cerebrospinal fluid concentrations. This study suggests Buparlisib monotherapy is not effective for treating these aggressive brain tumors.
Area of Science:
- Oncology
- Pharmacology
Background:
- Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited therapeutic options.
- The phosphoinositide 3-kinase (PI3K) pathway is a promising target in B-cell malignancies, but its role in CNS lymphomas is unknown.
Purpose of the Study:
- To evaluate the pre-clinical and clinical efficacy of the pan-PI3K inhibitor Buparlisib in patients with CNS lymphomas.
- To assess Buparlisib's pharmacokinetics, clinical outcomes, and safety profile in this patient population.
Main Methods:
- Determination of Buparlisib EC50 in a primary CNS lymphoma cell line.
- Prospective trial enrolling four patients with recurrent CNS lymphoma.
- Evaluation of Buparlisib plasma and cerebrospinal fluid (CSF) pharmacokinetics, clinical response, and adverse events.
Main Results:
- Buparlisib was detected in plasma and CSF two hours post-treatment, but median CSF concentration was below the determined EC50.
- Treatment was generally well-tolerated, with common toxicities including hyperglycemia, thrombocytopenia, and lymphopenia.
- Buparlisib monotherapy did not result in significant clinical responses, with a median time to progression of 39 days.
Conclusions:
- Buparlisib monotherapy demonstrated limited efficacy in patients with recurrent CNS lymphoma.
- The observed low CSF concentrations of Buparlisib may explain its lack of therapeutic effect.
- Further investigation into PI3K pathway inhibition in CNS lymphomas may require different therapeutic strategies or combination approaches.
