Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study

Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetodax in a phase I study of relapsed/ refractory non-Hodgkin lymphoma (NHL). Complete response (CR) as observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldensfrom macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts. Patients and Methods: All patients (n = 106) received venetodax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated. Results: At a median follow-up of 38.5 months (range, 30.0-46.5), the median PFS for all 106 patients was 5.4 (95% confidence interval (CI), 3.5-8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7-27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year. Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.

Automated summary

In this study, all patients received venetoclax monotherapy at doses of 200 to 1200 mg daily and were evaluated for ORR, PFS, DoR, and AEs. Venetoclax monotherapy was found to have a manageable safety profile and achieve durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieved CR. Further research is needed to explore combination strategies to enhance the durability of response to venetoclax.