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Venetoclax plus rituximab is superior to bendamustine-rituximab in patients with relapsed/refractory chronic lymphocytic leukaemia

Results of the phase III MURANO trial show that venetoclax in combination with rituximab more than doubles the likelihood that patients with relapsed/refractory chronic lymphocytic leukaemia (r/r CLL) are alive and free of progression at two years compared to patients treated with bendamustine-rituximab (BR). Key secondary endpoints, including overall survival (OS), objective response rate (ORR) and complete response (CR) rate were also consistently and significantly improved with venetoclax-rituximab (VR). Furthermore, VR induced minimal residual disease (MRD) negativity in the peripheral blood in 83.5% of patients as compared to 23.1% for the BR arm, a rate that was never attained before in clinical studies in r/r CLL.

Venetoclax is an orally administered, highly selective, potent Bcl-2 inhibitor. Venetoclax was previously shown to induce high response rates when given as monotherapy to patients with r/r CLL. The phase III MURANO trial enrolled 389 patients whose CLL had persisted or recurred after at least one previous course of treatment. Half of the patients were randomly assigned to VR (N=194) and the other half was treated with BR (N=195). In the VR arm, a 4- or 5-week graduated dose ramp-up of venetoclax from 20 to 400 mg daily was used to mitigate the potential tumour lysis syndrome (TLS) risk. From week 6 onwards, monthly rituximab (IV 375 mg/m2 first dose, then 500 mg/m2) was added for six 28-day cycles. Patients continued with daily venetoclax at a dose of 400 mg for a maximum of 2 year, or until disease progression (whichever first). In the BR arm, patients were given bendamustine (IV 70 mg/m2) on days 1 and 2 of six 28-day cycles. Rituximab was given at the same dosing as in the VR arm. The primary endpoint of the trial was investigator (INV)-assessed PFS.

Patient and disease characteristics were well balanced between both study arms. The median age of patients in the study was 65 years, about 60% received 1 prior therapy and approximately 15% of patients were fludarabine refractory. A quarter of patients in the study harboured a del(17p) and 68% of patients had unmutated IGHV genes. With a median follow-up of 23.8 months, the PFS was found to be significantly better with VR than with BR (median PFS not reached vs. 17 months; HR[95%CI]: 0.17[0.11–0.25], p< 0.0001). The 24-month estimates for PFS were 84.9% and 36.3% for VR and BR, respectively. The PFS benefit of VR over BR was seen in all investigated subgroups, irrespective of age, the presence of a del(17p), risk status, the number of prior therapies, and the p53 or IGHV mutational status. Also the secondary objectives of the study showed consistent improvements with VR compared to BR. The 2-year OS rate with VR was 91.9%, which was significantly better than the 86.6% seen with BR (HR[95%CI]: 0.48[0.25-0.90]; p= 0.0186). The investigator assessed ORR was 93.3% with VR as compared to 67.7% seen with BR (p< 0.0001). In the VR arm, 26.8% of patients obtained a CR compared to a CR rate of 8.2% with BR (p< 0.0001). At all time points, a higher rate of MRD negativity in the peripheral blood was seen with VR compared to BR and this MRD negativity was also more durable with VR. Overall, peripheral blood MRD negativity was seen in 83.5% of VR patients as compared to 23.1% in the BR arm (p< 0.0001).

The rate of serious adverse events (AEs) was comparable between both arms (46% vs. 43%). AEs with grade 3/4 severity were reported in 82% of the VR treated patients as compared to 70% in the BR arm. Consistent with known safety profiles of the drugs, grade 3/4 neutropenia was more frequent in the VR arm (58% vs. 39%) but there was no increase in febrile neutropenia or in the rate of grade 3/4 infections. In the VR arm, 3% of grade 3/4 tumor lysis syndrome (TLS) was reported (vs. 1% with BR). AEs leading to death were seen in 10 patients under VR and in 11 under BR.

In summary, results of MURANO show that VR is associated with a significant 83% reduction in the risk of disease progression or death compared to BR. This PFS benefit was seen in all investigated subgroups, including in patients with a del(17p), or a TP53 mutation. VR also induced a significantly higher rate of CRs compared to BR and obtained MRD negativity in more than 80% of the patients. Compared to BR, VR was also associated with a clinically meaningful improvement in OS. The safety profile of VR was consistent with the known safety profile of both drugs, with a low rate of TLS.


Seymour J, Kipps T, Eichhorst B Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study. Presented at ASH 2017; Abstract #LBA-2.

Speaker John Seymour


Prof.John F Seymour, MBBS, PhD, Peter MacCallum Centre & Royal Melbourne Hospital, Melbourne, Australia


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