Combination targeted therapy for relapsed diffuse large B-cell lymphoma

Key message:

In this single-center, phase Ib/II study, the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) was evaluated in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The study demonstrated an objective response rate of 54%, with complete responses achieved in 38% of patients. ViPOR demonstrated high efficacy in germinal center B-cell (GCB) tumors with MYC and BCL2 translocations, resulting in a 2-year progression-free survival rate of 47% in these patients compared with 8% in patients without translocations. Complete responses were particularly observed in patients with non-GCB DLBCL and high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (HGBCL-DH-BCL2). The 2-year progression-free survival and overall survival were 34% and 36%, respectively. Additionally, among patients previously treated with CAR T-cell therapy, ViPOR was associated with a 2-year progression-free survival of 30%.

Safety data revealed grade 3 or 4 neutropenia, thrombocytopenia, and anemia in 24%, 23%, and 7% of cycles, respectively. In addition, grade 3 or higher hypokalemia occurred in 28% of patients, highlighting the need for aggressive monitoring and electrolyte replacement. The promising efficacy of ViPOR in patients with relapsed or refractory non-GCB DLBCL and HGBCL-DH-BCL2 suggests the need for larger validation studies.

SUMMARY

BACKGROUND

The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs targeting major survival pathways, but it remains unknown whether targeting multiple survival pathways can be curative in DLBCL.

METHODS

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

RESULTS

In a phase 1b study of 20 patients (10 with DLBCL), a single dose-limiting toxicity of grade 3 intracranial hemorrhage was observed, leading to venetoclax 800 mg being the recommended dose for phase 2. Phase 2 enrolled 40 patients with DLBCL. Toxicities observed in all patients included grade 3 or 4 neutropenia (in 24% of cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses were observed in 54% of 48 evaluable patients with DLBCL, and complete responses were observed in 38%; Complete responses were observed exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with MYC and BCL2 or BCL6 (or both) rearrangements. Circulating tumor DNA was undetectable in 33% of patients at the end of ViPOR therapy. At a median follow-up of 40 months, the 2-year progression-free survival and overall survival rates were 34% (95% confidence interval (CI) 21 to 47) and 36% (95% CI 23 to 49), respectively.

CONCLUSIONS

ViPOR treatment was associated with durable remission in patients with specific molecular subtypes of DLBCL and predominantly reversible adverse events.

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DOI: 10.1056/NEJMoa2401532

Link: https://www.nejm.org/doi/10.1056/NEJMoa2401532

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