Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma

Abstract

Background: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.

Methods: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.

Results: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.

Conclusions: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Figure 1:. ViPOR Treatment Regimen and Clinical Activity.

A). Schematic of the survival pathways targeted by the ViPOR regimen; B). Schematic of ViPOR agent dosing and post-treatment surveillance monitoring; C). Waterfall plot of DLBCL patients showing the percent change in the sum of the product of the diameters (SPD) following ViPOR therapy as compared to baseline as assessed by computed tomography (CT); D). Kaplan-Meier analysis of progression-free survival starting at the on-study date for all DLBCL patients. *One non-GCB DLBCL, NOS patient died in remission at 31 months from COVID-19 infection; E). Kaplan-Meier analysis of duration of response starting at the response date and separated by complete or partial response to ViPOR. *Two patients (1 in complete response and 1 in partial response) died without disease relapse or progression and were censored at the time of death; F). Kaplan-Meier analysis of progression-free survival starting at the on-study date and separated by histologic DLBCL subtype.

Figure 2:. Adverse Events.

Depicted are all adverse events with an attribution of at least possibly related to ViPOR therapy and occurring in ≥20% of patients. Adverse events are depicted in descending order of frequency and broken down by grade of toxicity encountered.

Figure 3:. Molecular Correlates of ViPOR Response.

A). The response to combinations of venetoclax and lenalidomide in a 10 × 10 matrix for the OCI-Ly10 ABC DLBCL cell line using normalized cell viability (top) or the calculated ΔBliss synergy score (bottom); B). Heatmaps displaying the calculated ΔBliss synergy score for each combination of indicated ViPOR drug doublets in four ABC DLBCL cell lines in a 10 × 10 matrix; C). Relative luminescence units (RLU) are displayed for cleaved caspase 3/7 measured in the indicated ABC DLBCL cell lines in culture with ViPOR agents singly or in combination for 2 to 24 hours; D). The complete response rate of ViPOR-treated patients is displayed for tumor biopsy grouped by LymphGen genetic subtype (left), or by cell-of-origin gene expression-assigned subtype (right). Pie charts are scaled to the total number of biopsies assigned to each subtype and display the percent of patients with complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD); E). Normalized cell viability of indicated GCB DLBCL cell lines treated with dilutions of the BCL2 inhibitor venetoclax (0.01-10.0uM). Assignment of GCB cell lines to LymphGen genetic subtypes is indicated. The EZB subtype can by further subdivided into EZB-MYC⁺ with both MYC and BCL2 translocations and EZB-MYC⁻ that has only one or neither of these translocations.