Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

N Engl J Med · 2018389 patients

Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. N Engl J Med. 2018. 378:1107-1120

A newer report of this study has been published: The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL (2025)

Study type: Clinical trial
Study name: MURANO
Phase: Phase 3
Design: Randomised, open-label trial
Sample size: 389 patients
Source: N Engl J Med · 2018
Trial registration: NCT02005471

In plain words

In this study, patients with chronic lymphocytic leukaemia (CLL) whose disease had come back or had not responded to earlier treatment received either venetoclax with rituximab or bendamustine with rituximab. After 2 years, about 85% of patients in the venetoclax group were still free of disease progression, compared with about 36% in the comparison group. This benefit was also seen in patients with the 17p deletion (a genetic change linked to harder-to-treat disease). A drop in white blood cells (neutropenia) was more common with venetoclax, but infections and fever with low white blood cells were seen less often.

Key results

84.9% vs 36.3%

2-year progression-free survival rate (investigator-assessed)

HR for progression or death 0.17; 95% CI 0.11–0.25; P<0.001

32 events in 194 patients vs 114 events in 195 patients

Progression or death events

Venetoclax–rituximab vs bendamustine–rituximab

81.5% vs 27.8%

2-year PFS in patients with 17p deletion

HR 0.13; 95% CI 0.05–0.29

85.9% vs 41.0%

2-year PFS in patients without 17p deletion

HR 0.19; 95% CI 0.12–0.32

3.1% (6 of 194 patients)

Grade 3 or 4 tumour lysis syndrome (venetoclax–rituximab group)

Drugs in this study:Bendamustine Rituximab (Rituxan/MabThera)Venetoclax (Venclexta)

Dose and schedule cards

Venetoclax + rituximab (MURANO)

Relapsed or refractory CLLCycle length: Every 28 daysOn the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

Relapsed or refractory CLL

Drug	Dose	Route	Schedule
5-week ramp-up
Venetoclax	20, 50, 100, 200 and then 400 mg (one step each week)	Oral, with food	Weeks 1–5
After 7 days of venetoclax 400 mg (6 cycles)
Rituximab	375 mg/m² in cycle 1; 500 mg/m² in cycles 2–6	IV	Day 1 of each cycle
Continuation
Venetoclax	400 mg once daily	Oral	24 months from Day 1 of rituximab cycle 1

Cycle length: Every 28 days
Duration: Venetoclax 24 months (after the ramp-up); rituximab 6 cycles

TLS prophylaxis, CYP3A interactions and hepatitis B screening as in “Shared safety points” above.

On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

Venetoclax + rituximab (MURANO)

Relapsed or refractory CLL/SLLCycle length: Every 28 daysOn the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

Relapsed or refractory CLL/SLL

Drug	Dose	Route	Schedule
5-week ramp-up
Venetoclax	Week 1: 20; week 2: 50; week 3: 100; week 4: 200; from week 5: 400 mg	Oral, with food and water	Once a day
After 7 days of venetoclax 400 mg
Rituximab	Cycle 1: 375 mg/m²; cycles 2 to 6: 500 mg/m²	IV	Day 1, 6 cycles

Cycle length: Every 28 days
Duration: Venetoclax for 24 months from day 1 of rituximab cycle 1

On the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Venetoclax + rituximab (194 patients)

Venetoclax with a 5-week ramp-up from 20 mg orally once daily with weekly increases to 400 mg; then 400 mg daily from week 6 (day 1 of cycle 1 of combination therapy) until progression or for up to 2 years. Rituximab 375 mg/m² IV on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6 (28-day cycles).

2Bendamustine + rituximab (195 patients)

Bendamustine 70 mg/m² IV on days 1 and 2 of each 28-day cycle for 6 cycles + rituximab 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6. Crossover to venetoclax–rituximab was not planned in the original design.

Source of the regimen details: ClinicalTrials.gov NCT02005471 (doses and inclusion criteria)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with relapsed or refractory CLL (iwCLL criteria) after 1 to 3 prior lines of therapy, including at least one standard chemotherapy-containing regimen; prior bendamustine only if the duration of response was at least 24 months; ECOG 0 or 1 and adequate bone marrow, renal and hepatic function.

Endpoints

Primary endpoint: investigator-assessed progression-free survival (PFS). Secondary endpoints included PFS assessed by an independent review committee and other secondary efficacy endpoints.

Safety and side effects

The rate of grade 3 or 4 neutropenia was higher with venetoclax–rituximab than with bendamustine–rituximab, but the rates of grade 3 or 4 febrile neutropenia and of infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumour lysis syndrome in the venetoclax–rituximab group was 3.1% (6 of 194 patients).

Clinical significance and place in guidelines

Based on the abstract, venetoclax plus rituximab markedly improved progression-free survival in relapsed or refractory CLL compared with bendamustine–rituximab, including in patients with 17p deletion. Regulatory approvals and the regimen's place in current treatment guidelines should be checked separately, as they are not mentioned in the abstract.

Limitations

The trial was open-label and the primary endpoint was investigator-assessed (although confirmed by independent committee assessment). The trial design did not include crossover to venetoclax–rituximab for control-group patients with disease progression. Median follow-up was 23.8 months.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.