Preemptive Therapy with Venetoclax for High-Risk Stage a CLL Patients: First Analysis of Prevene, a Phase II Trial of the Filo Group

The current standard of care for CLL Binet stage A patients is still the “watch and wait” strategy. Recently, 2 RCTs evaluating an immunochemotherapy by FCR (Herling 2020) or Ibrutinib (Langerbeins 2022) have failed to improve the prognosis of early-stage CLL patients. By contrast to ibrutinib, venetoclax demonstrated in monotherapy a high overall response rate (ORR) with achievement of complete responses (CR) with undetectable MRD in relapsed/refractory CLL patients with adverse prognostic factors (including TP53 alterations). In CLL, the achievement of CR with MRD negativity has emerged as a major goal to improve the prognosis and to optimize the duration of the treatment. For stage A CLL patients, the objective of the treatment is to achieve a CR with undetectable MRD to possibly eradicate the disease. Based on these data, we conducted an open label, single arm, multicenter, phase II trial evaluating a fixed-duration and MRD guided treatment with venetoclax monotherapy for untreated, high-risk, Binet stage A CLL patients

High-risk Binet stage A patients were defined by unmutated IGHV status and 2 or more of the following parameters at diagnosis: (1) lymphocytosis > 13 G/L, (2) CD38 > 7%, (3) B2 microglobulin > 2.5 mg/L. Patient with del(17p)/TP53 mutation could be included. Venetoclax was administered according to the usual schedule with a duration based on the centralized MRD results. For patient achieving a CR with MRD < 0,01% in bone marrow (BM) at month 12 (M12), treatment was stopped at M18. For CR or PR patients at M12 with BM MRD > 0.01%, treatment was continued until M24. All patients stopped the treatment after M24. The primary endpoint was the CR rate (IWCLL guidelines) with BM MRD < 0.01% (as determined by 8-color flow cytometry) at M12. The main secondary endpoints were safety, ORR at M12 and M24, proportion of responding patients (PR or CR) with BM MRD > 0.01% at M12 achieving a BM MRD < 0.01% at M24, proportion of patients in CR with BM MRD < 0.01% at M12 stopping treatment at M18 and overall survival (OS), progression-free survival (PFS), event-free survival (EFS, defined as time from entry on study to disease recurrence or progression or permanent treatment discontinuation due to toxicity or death), time to next treatment (TTNT), duration of response (DOR, defined as the time from documentation of response to disease progression) and quality of life according to EQ-5D™. The statistical hypothesis was to obtain a CR rate with BM MRD < 0.01% at M12 over 30%; a CR rate with BM MRD < 0.01% at M12 of less than 15% was considered as unacceptable. The expected accrual was 82 patients.

Forty-four patients were included between 05/19 and 05/23. Inclusions were prematurely stopped because of a low accrual rate. Median age [IQR] was 62.8 yrs [56.4-70.3] and 65.9% of the pts were male. All pts were Binet stage A with unmutated IGVH. Median lymphocytosis was 29.7 G/L and RMH score was 5 for 81.8% of the patients. Median creatinine clearance was 87.9 ml/min and median B2microglobulin was 2.8 mg/L. 5 (11.5%) patients had a positive DAT and 7 (15.9%) had a del 17p (FISH).

In ITT analysis, 13/44 (29.5%) patients were in CR/CRi with BM MRD < 0.01% [95%CI: 16.8-45.2%] at M12 and 13/37 (35.1%) [95%CI 20.2-52.5%] in per protocol analysis. Among the 19 patients in PR or CR with MRD ≥ 0,01% at M12, 15 were evaluable at M24 and 26.7% (4/15) [95%CI 7.8- 55.1%] achieved a BM MRD < 0.01% at M24. With a median follow-up of 51.8 mo, the estimated PFS [95%CI] was 94% [87 - 100] and 91% [81 - 100] at 2 yrs and 3 yrs respectively. OS at 24 mo was 100% and 93 mo at 36 mo (3 deaths: 1 progression, 1 pneumoniae, 1 dementia). Only 4 patients received a subsequent therapy, including one Richter transformation. Median EQ-5D™ score at inclusion was 78 [67.5 – 90.0], 75 [70 - 90] at M18 and 80 [71.3 - 90] at M24. Among the patients, 65.9% presented a grade 1 AE, 56.8% a grade 2, 36.4% a grade 3 and 11.4% a grade 4. Most of the grade 3-4 AEs were infectious or gastro-intestinal.

Interstingly, among the 27 pts with BM and blood MRD data at M12, 33.3% (9/27) had a BM MRD level inferior to that measured in peripheral blood ; these unexpected findings were confirmed at M24 since 40% of the 15 pts had a value of BM MRD < blood MRD level.

Treatment with venetoclax monotherapy in previously untreated high-risk Binet stage A CLL is feasible, but at this stage its value cannot be demonstrated. More prolonged follow-up is needed to estimate a possible benefit for patients. Data will be updated at the time of meeting presentation