Final Analysis of the Safety and Efficacy of Venetoclax in Combination with Pola-R-CHP for Untreated High-Risk BCL-2-Positive B-Cell Lymphoma Including Double/Triple Hit Lymphoma
Authors: Diefenbach Catherine S. , Zelenetz Andrew D. , Herbaux Charles , Tani Monica , Houot Roch , Bastos-Oreiro Mariana , Tilly Hervé , Gastinne Thomas , Thieblemont Catherine , Leung Wilfred , Hatzi Katerina , Kesavan Murali , Barlera Simona , Boyer Michelle , Morschhauser Franck 
Published: December 2024

Background: Venetoclax (Ven) is an oral B-cell lymphoma 2 (BCL-2) inhibitor which has shown activity combined with rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O), and prednisolone (P; R-CHOP) in first line diffuse large B-cell lymphoma (DLBCL; Morschhauser et al. Blood 2021).

In the Phase III POLARIX study, polatuzumab vedotin (Pola)-R-CHP had a longer progression-free survival (PFS) versus R-CHOP, establishing Pola-R-CHP as standard of care for untreated patients (pts) with DLBCL and BCL-2 overexpression by immunohistochemistry (BCL-2 IHC+; Morschhauser et al. EHA 2022). The BO42203 trial (NCT04790903) explored whether Ven+Pola-R-CHP could further improve outcomes in this population; early results showed acceptable safety and promising efficacy (Zelenetz et al. ASH 2023). Here, we report the final analysis of the BO42203 trial.

Methods: BO42203 was a Phase Ib, open-label, multicenter trial of pts with untreated BCL-2 IHC+ DLBCL (including Grade 3b follicular lymphoma). Pts enrolled had an International Prognostic Index (IPI) score of 2-5, and BCL-2 IHC+ defined as ≥50% expression (by local pathology).

The primary endpoint was to determine the recommended Phase II dose (RP2D) for Ven+Pola-R-CHP based on the rate of dose-limiting toxicity (DLT) during the first 2 cycles (42 days [D]). Secondary endpoints included safety/tolerability, PET-CT based objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and PFS.

Pts were enrolled in 5 cohorts (n=10 pts each). Safety data were reviewed by an internal monitoring committee (IMC) who could alter the Ven dose/schedule for the next cohort. Pts received 6 21-D treatment cycles. Pola-R-CHP was administered on D1 of each cycle at the following doses: Pola 1.8mg/kg, R 375mg/m2, C 750mg/m2, H 50mg/m2, and P 100mg/D for 5 Ds. All pts in Cohort 1 were assigned to Ven 800mg/D for 5 Ds/cycle; doses started on D4 of Cycle 1 and D1 of subsequent cycles (Schedule A) with optional escalation to 10 Ds/cycle from Cohort 2 onwards (Schedule B), depending on IMC review.

Results: At data cut-off (May 21, 2024), 5 cohorts were enrolled (n=50). At baseline, the median age was 64.5 years, 20 (40.0%) pts were female, and 5 (10.0%) had an Eastern Cooperative Oncology Group performance status of 2. High-risk features were prevalent: 45 (90.0%) pts had Ann Arbor Stage III-IV; 38 (76.0%) had an IPI score of ≥3; and 7 (14.0%) had high-risk cytogenetics (double/triple hit lymphoma [DHL/THL]). Median duration of follow-up was 15.5 months (range: 1.7-34.0).

Forty-two pts completed study treatment. Reasons for discontinuation included death (n=7: 5 due to progressive disease [PD], 2 due to adverse events [AEs]) and withdrawal by patient (n=1). Forty-eight pts completed the DLT period; 2 pts withdrew prior to this due to meningitis and a COVID-related AE. No DLTs were observed. Grade ≥3 myelosuppression was observed in Cohort 1 after the DLT period: neutropenia (n=5 pts [50.0%]), neutrophil count decreased (n=2 [20.0%]), and febrile neutropenia (n=1 [10.0%]). Hence, after IMC review of Cohorts 1-3, Schedule A was maintained/administered for all future pts.

All pts had ≥1 AE; 37 (74.0%) and 24 (48.0%) pts had ≥1 Grade ≥3 AE and serious AE (SAE), respectively. The most common (≥15%) Grade ≥3 AEs included: neutropenia (46.0%) and febrile neutropenia (18.0%). Two (4.0%) pts died due to treatment-related SAEs (investigator-assessed; arrhythmia/cardiac arrest [related to Ven] and sepsis [related to Ven+Pola-R-CHP]). AEs leading to dose modification/delay of any drug occurred in 20 (40.0%) pts (Ven: 19 [38.0%]; R: 17 [34.0%]; Pola: 16 [32.0%]; C and H: 15 [30.0%] each; P: 6 [12.0%]); 7 (14.0%) pts had an AE that led to discontinuation of any study drug.

The end of treatment PET-CT based ORR and CR were 86.0% and 82.0% (n=50), respectively (including all pts with DHL/THL [n=7; CR: 100%]). Two (4.0%) pts had PD, and 5 were not assessed (2 pts died before PD assessment; 3 pts had discontinued treatment). The median DOR was not estimable (NE; 95% confidence interval [CI]: NE). The 1-year PFS and overall survival rates were 75.5% (95% CI: 61.1, 90.0) and 91.7% (95% CI: 83.9, 99.5), respectively.

Conclusions: Ven 800mg/D for 5 Ds/cycle plus Pola-R-CHP was determined as the RP2D for untreated BCL-2 IHC+ DLBCL. In this final analysis, no new safety signals were observed. In this high-risk group of pts, high CR rates were seen across all cohorts, including pts with DHL/THL.