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Clinical superiority of fixed duration treatment with venetoclax and rituximab over bendamustine-rituximab in patients with relapsed/refractory chronic lymphocytic leukemia

The phase III MURANO trial assessed the efficacy and safety of venetoclax in combination with rituximab (VenR) given for a fixed duration in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Earlier this year, a pre-planned analysis (with the majority of patients still on study treatment) indicated a significantly longer progression free survival (PFS) with VenR compared to bendamustine-rituximab (BR). At ASH 2018, an update of this trial was presented with more than one year of additional follow-up. This updated analysis, with all patients being off study drug, the PFS benefit of VenR over BR was confirmed. In addition, clinically meaningful improvements in overall survival (OS) were reported with VenR. A high proportion of VenR treated patients obtained undetectable levels of minimal residual disease (uMRD) and MRD-negativity at the time of treatment cessation was found to be a strong predictor of a durable PFS off therapy. Overall, these updated data establish VenR for a fixed period of time as a safe and effective treatment option for R/R CLL.

In total, 389 patients with R/R CLL were randomized to receive 6 cycles of VenR followed by Ven 400mg once daily for a total of 2 years, or 6 cycles of BR. The primary endpoint was investigator-assessed PFS, with the rate of uMRD as key secondary objective. The median patient age in the study was 65 years, two thirds of patients had a lymphocyte count of at least 25 x109/L and about 40% harbored a del(17p) and/or a TP53 mutation. Just short of 60% of patients received VenR or BR as second line treatment. As of May 8 2018, all patients were off treatment. For BR, 154 (79%) had completed 6 cycles, while in the VenR arm, 174 (90%) patients completed the VenR combination phase of whom 130 (67%) also completed 2 years of Ven. The remainder of the patients had progressive disease (PD) (11%), died (1%), or withdrew due to adverse events (AEs) (15%) or for another reason (6%).

After a median follow-up of 36 months (with a median of 9.9 months after completion of 2 years Ven therapy), the PFS with VenR remained significantly superior to BR. With VenR the median for PFS was not yet reached as compared to 17 months with BR (HR[95%CI]: 0.16[0.12-0.23]; p< 0.0001). The 3-year PFS estimates were 71.4% and 15.2% with venR and BR, respectively. The magnitude of this PFS benefit with VenR over BR was seen in all investigated subgroups, irrespective of age, the number of prior therapies and the presence of a del(17p) or a TP53 mutation. In addition, a clinically meaningful improvement in OS was seen with VenR over BR after 3 years (3-year OS rate: 87.9% vs. 79.5%; HR[95%CI]: 0.50[0.30-0.85]). Of note, most patients with disease progression on BR received subsequent therapy with ibrutinib or (46/91) or venetoclax (7/91). For patients who completed 2 years of Ven (N= 130), 6- and 12-month PFS estimates were high at 92% and 87%, respectively.

Importantly, only 16 out of 130 patients developed disease progression after the cessation of Ven. Fourteen of these 16 patients were MRD-positive at >1% in the peripheral blood at the time of Ven cessation. This makes MRD positivity at the time of Ven cessation the strongest predictor for disease progression (p< 0.0001). In addition, also the presence of a del(17p), or a TP53 mutation were predictive for progression (10/16 progressing patients had a del(17p) or a TP53 at baseline).

During Ven single agent: 17/171 patients (10%) had an AE leading to drug withdrawal and 7/171 patients (4%) had an AE leading to dose reduction. In 44/171 patients (26%) Ven had to be interrupted due to an AE. Fatal AEs were reported in 7 patients (4%). Grade 3/4 AEs occurred in 35% of patients, with neutropenia (12%), anemia (3%), and thrombocytopenia (2%) as the most frequent event.

In conclusion, this updated analysis of the MURANO trial, with all patients being off treatment and a median follow-up of 3 years, demonstrates a continued substantial PFS and OS benefit with VenR over BR. The rate of CLL progression in the first 12 months after stopping Ven was relatively low (13%), supporting the feasibility and safety of a time-limited VenR duration.


J. Seymour, et al. MURANO Trial Establishes Feasibility of Time-Limited Venetoclax-Rituximab (VenR) Combination Therapy in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Presented at ASH 2018; Abstract 184.

Speaker John Seymour


John F. Seymour, MBBS, PhD, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia


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