The Phase Ib VenObi CNS Study: Chemotherapy-Free Treatment with Venetoclax and Obinutuzumab for Relapsed/Refractory Primary Large B-Cell Lymphoma of the Central Nervous System

TL;DR

A chemotherapy-free treatment combining venetoclax and obinutuzumab showed promise in treating relapsed/refractory central nervous system lymphoma, with some patients achieving remission.

Contribution

This study is the first to evaluate the chemotherapy-free combination of venetoclax and obinutuzumab in relapsed/refractory PCNSL patients.

Findings

Venetoclax and obinutuzumab penetrated the central nervous system, with CSF concentrations measured.

Two out of five patients achieved complete remission, with a median response duration of 6.5 months.

The treatment was found to be feasible and tolerable in selected patients.

Abstract

Despite substantial advances in the treatment of primary large B-cell lymphoma of the central nervous system (PCNSL), up to one-third of patients fail first-line treatment due to toxicity or early disease progression, and up to 50% of patients eventually relapse, despite achieving complete remission after first-line treatment. In the relapsed/refractory setting (rrPCNSL), the standard of care is not established, and prognosis remains poor. The most common genetic imbalance in PCNSL includes the B-cell lymphoma 2 (BCL-2) locus. The aim of this investigator-initiated phase Ib trial was to assess the pharmacokinetics of the BCL-2 inhibitor venetoclax and the CD20-antibody obinutuzumab in rrPCNSL. We demonstrated that both drugs could penetrate into the central nervous system compartment. Moreover, this chemotherapy-free combination treatment was feasible, tolerable, and may provide durable responses in selected patients.

Background/Objectives: Relapsed and refractory (rr) primary large B-cell lymphoma of the central nervous system (PCNSL) has a dismal prognosis, and the standard of care is not established. The most common genetic imbalance includes the B-cell lymphoma 2 (BCL-2) locus. Methods: We planned a bi-centric phase Ib dose-escalation study with the chemotherapy-free combination of the BCL-2 inhibitor venetoclax and CD20 antibody obinutuzumab for rrPCNSL patients in Germany. The intended treatment consisted of 6 cycles of fixed-dose obinutuzumab at 1000 mg intravenously every 3 weeks, and an oral daily dose of 600, 800, or 1000 mg venetoclax, depending on the planned dosing group, followed by a 12-month venetoclax maintenance period. The primary endpoint was the pharmacokinetics of venetoclax and obinutuzumab in cerebrospinal fluid (CSF). Results: This study was prematurely terminated after registration of 5/15 (33%) patients in dosing group 1 (600 mg oral daily dose of venetoclax) between May 2020 and November 2021. The mean ratio of the concentration of venetoclax in CSF over peripheral blood was 0.55% (±0.28 standard deviation (SD)) and 0.25% (±0.23 SD) for obinutuzumab. Two of five patients achieved complete remission, and each one patient achieved partial remission and stable disease as best response. The median duration of response was 6.5 months (range 0.7–47). Conclusions: Venetoclax and obinutuzumab can penetrate into the central nervous system, but the CSF concentration did not correlate with the outcome. The combination is feasible, tolerable, and may lead to durable responses in selected rrPCNSL patients.

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