Obinutuzumab, Lenalidomide and Venetoclax for the Initial Treatment of Patients with Advanced-Stage Follicular Lymphoma: Primary Analysis of an Investigator-Initiated Phase Ib/II, Multicenter Study (LEVERAGE)
Authors: Cheah Chan Y. , Johnston Amanda Jane , Wight Joel , Blombery Piers , Lewis Katharine L. , Bennett Rory , Xie Jing , Vlahos Stella , Gonzales Joyce , Binks Sally , Seymour John F. 
Published: December 2024

Background
Follicular lymphoma (FL) is the most common indolent lymphoma. The most widely used initial treatment is chemo-immunotherapy, which may result in acute and late toxicities. There is a need for effective novel treatments with favorable safety profiles.
Methods
We designed a phase Ib/II study of obinutuzumab (OBI), lenalidomide (LEN) and venetoclax (VEN) in patients (pts) with treatment-naïve FL. Key inclusion criteria included non-contiguous or bulky stage II-IV disease, meeting GELF criteria for treatment, adequate organ function and performance status. Treatment was divided into 2 phases, induction (6 x 28-day cycles) and maintenance (12 x 56-day cycles). During induction, pts received fixed doses of OBI (1000mg D1, 8, 15 cycle 1; D1 of C2-6) and LEN 20mg/d D1-21 from C2-6. VEN was given from C1-6 and the dose was escalated, according to a 3+3 design with 4 dose levels (DL) tested: DL 1: 400mg/d D1-10, DL 2: 800mg D1-10, DL 3: 400mg D1-28 and DL 4: 800mg D1-28. After 6 cycles, pts who attained complete response (CR) received OBI maintenance (1000mg every 8 weeks for 2 years). Pts who attained partial response (PR) received a further 6 cycles of LEN (10mg D1-28) and VEN (same dose as given in induction) in addition to OBI maintenance. Pts with stable disease (SD) or progressive disease (PD) discontinued study. Safety analysis and recommended phase 2 dose (DL 4 - VEN 800mg daily D1-28) has been presented previously (Cheah ASH 2023). This analysis reports the primary endpoint of phase II: intention to treat CR rate by investigator assessment at end of induction (EOI) by Lugano 2014 criteria. Key secondary endpoints included safety, overall response rate (ORR), progression free survival (PFS), overall survival (OS), and duration of response (DOR).
Results
As of 13th June 2024, 50 pts have been enrolled and all have completed EOI. Eighteen pts were treated in dose escalation (3, 6, 3 and 6 at DL 1-4, respectively) and 32 in expansion phase. Baseline characteristics included: median age 60 years (range 33 - 78), stage IV 72%, B symptoms 16%, male 50%, PRIMA-PI score was 0, 1 and 2 in 42, 42 and 16% respectively.
The CR rate was 86% among pts treated at RP2D (primary endpoint) and 83% among all pts. The ORR was 92% for both the RP2D cohort, and all pts. At a median follow-up of 18.3 months, the actuarial 2-year PFS and OS rates were 92% (95% CI: 80, 97) and 100% respectively. At a median follow-up of 16.1 months, the actuarial 12-month DOR rate was 95% (95% CI: 81,98). One pt died from T-cell prolymphocytic leukemia while in CR from FL at 30 months. Among the 4 pts with PD, 3 biopsies were performed at PD: 3 had histologic transformation to diffuse large B-cell lymphoma while the remaining patient did not undergo a biopsy.
In the entire cohort, the most common any grade AEs were neutropenia (72%) diarrhea (52%), upper respiratory infection (48%), nausea (38%), rash (38%), fatigue (34%), thrombocytopenia (32%) and infusion reaction (30%). The most common grade ≥3 AEs were neutropenia (70%) with febrile neutropenia 4%, thrombocytopenia (24%), rash (6%) and syncope (6%). Two pts developed biochemical (but not clinical) TLS, both on C1D1. The median relative dose intensity was &gt;90% for all 3 agents. 15 pts (30%) prematurely discontinued study treatment, 11 during induction and 4 during maintenance. The reasons for discontinuation during induction were PD (n=4), hematologic toxicity (n=4), infusion reaction, ALT elevation and enterocolitis with sepsis (one each). The reasons for discontinuation during maintenance were infections (n=3) and T-PLL (n=1).
Molecular characterization was performed on the entire cohort at baseline from plasma cell free DNA (cfDNA) using CAPP-Seq (KAPA NHL; Roche Diagnostics). 47/50 pts had detectable cell free DNA (cfDNA) for analysis (average variant allele frequency 7.4%). Frequently detected mutations included CREBBP (n=30), TNFRSF14 (n=21) and EZH2 (n=19). BCL2 aberrant somatic hypermutation was detectable in 41 pts with two pts harboring variants previously associated with VEN resistance (R129L and L119V). Two pts had TP53mutations with one achieving CR at EOI. All pts with detectable tumour cfDNA (n=47) had phased variants suitable for sensitive longitudinal cfDNA monitoring.
Conclusion
The combination of OBI, LEN and VEN is a highly active combination in patients with treatment-naïve high tumor burden FL, although cumulative myelosuppression and infectious toxicity had an impact on deliverability.