MURANO: What the Leukemia Trial Found

What CLL is, and why it is treated late

Chronic lymphocytic leukemia is a disorder of mature-looking but immunologically immature lymphocytes. NCI describes it as a steady accumulation of those cells in the blood, bone marrow, and lymph tissue.

It usually starts quietly. NCI describes a course that runs from an indolent rise in lymphocyte count, with nothing else obviously wrong, to widespread lymph node enlargement with failing blood counts. Bleeding and infection from those failing counts are a major cause of death.

Because early CLL often does not need treating, watchful waiting is standard. NCI cites a meta-analysis of randomized trials showing no survival benefit for immediate over delayed therapy in early-stage disease.

When treatment is needed, it has historically meant chemotherapy given with an antibody, or a targeted pill taken indefinitely. MURANO tested a third option.

The drugs

Venetoclax blocks BCL2. BCL2 is an anti-apoptotic protein, meaning it stops cells from carrying out the self-destruct program they normally run when damaged. CLL cells overproduce it, which is central to their survival. Blocking it lets the cells die.

Rituximab is a monoclonal antibody against CD20, a protein on B cells.

The design question was not only whether the combination worked. It was whether treatment could stop.

How MURANO was built

MURANO was a randomized, open-label phase 3 trial. Its ClinicalTrials.gov record, NCT02005471, lists 389 participants.

All had CLL that had come back or stopped responding after earlier treatment.

They were assigned to one of two arms. The first was venetoclax for up to two years, plus rituximab for the first six months: 194 people. The second was bendamustine plus rituximab for six months: 195 people.

One design choice deserves flagging. The trial did not allow people in the bendamustine arm to cross over to venetoclax when their disease progressed.

The primary endpoint was investigator-assessed progression-free survival.

What it found

After a median follow-up of 23.8 months, 32 of 194 people in the venetoclax arm had progressed or died. In the bendamustine arm it was 114 of 195.

Two-year progression-free survival was 84.9% with venetoclax-rituximab and 36.3% with bendamustine-rituximab.

The hazard ratio for progression or death was 0.17, with a 95% confidence interval of 0.11 to 0.25 and a p-value below 0.001. That is one of the larger effects reported in this disease.

The benefit held across every clinical and biological subgroup examined.

That includes the hardest one. Among people with a deletion on the short arm of chromosome 17 — written del(17p), and long a marker of poor outcome — two-year progression-free survival was 81.5% with venetoclax-rituximab and 27.8% with bendamustine-rituximab. The hazard ratio was 0.13.

An independent review committee confirmed the progression-free survival finding.

What it costs

Grade 3 or 4 neutropenia — a severe drop in a type of infection-fighting white cell — was more common with venetoclax-rituximab.

But the complications that follow from neutropenia were less common, not more. Grade 3 or 4 febrile neutropenia, and infections, were lower with venetoclax than with bendamustine.

Grade 3 or 4 tumor lysis syndrome occurred in 3.1% of the venetoclax group, 6 of 194 people. Tumor lysis syndrome happens when cancer cells die so fast that their contents flood the bloodstream, overwhelming the kidneys and disturbing heart rhythm. It is the reason venetoclax is started at a low dose and increased in weekly steps, with fluids and blood monitoring.

What happened next

On 8 June 2018 the FDA approved supplements 4 and 5 to venetoclax's application, NDA 208573. Supplement 4 used MURANO as confirmatory data to convert an accelerated approval to regular approval.

The resulting indication covers patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy.

When to get checked

For anyone starting venetoclax, the ramp-up weeks are the risk window. Reduced urine output, muscle cramps, an irregular heartbeat, confusion, nausea, or vomiting during that period need same-day contact with the treating team.

Throughout treatment, fever is the signal that matters most. A temperature over 38 degrees Celsius, or 100.4 Fahrenheit, in someone with low neutrophils is an emergency rather than a wait-and-see.

For CLL itself, NCI's clinical summary sets out numeric thresholds that define progressive disease needing treatment. They are worth knowing because they explain why a team may watch rather than act:

• Hemoglobin below 10 g/dL, or platelets below 50 × 10⁹/L.
• A spleen 6 cm or more below the left rib margin, or one that is growing or causing symptoms.
• Lymph nodes 10 cm or more across, or growing, or causing symptoms.
• A lymphocyte count rising by 50% or more over two months, or doubling in under six months.

Outside those, the symptoms that should prompt a visit are painless swollen lymph nodes, drenching night sweats, unexplained fever, unintended weight loss, and fatigue that does not lift. Our overview of leukemia covers the main types.

The wider picture

About 22,760 new CLL diagnoses and 4,350 deaths are projected in the United States for 2026 — an American Cancer Society estimate published on SEER's page. SEER's own measurements put the median age at diagnosis at 71, with a third of new cases in people aged 65 to 74.

Five-year relative survival was 90.2% for people diagnosed from 2016 through 2022. In 1975 it was around 69%.

That is a group figure across every stage and genetic subgroup, and it does not forecast one person's course. Our page on active surveillance versus treatment covers why a high survival figure and a decision not to treat often go together.

What this trial cannot tell you

No crossover was allowed. That is a defensible design choice, but it means the gap between the arms is wider than it would be if people who progressed on bendamustine had been able to switch.

Median progression-free survival had not been reached in the venetoclax arm at this analysis, so its true length was unknown at publication.

The comparator was also already fading. Bendamustine plus rituximab was losing ground in relapsed CLL by 2018, so this is not a test against the strongest available alternative — in particular, not against continuous BTK inhibitor therapy.

The trial was open-label. Investigator-assessed progression was the primary endpoint, which is why the independent committee's confirmation matters.

Sources

• Seymour JF et al., N Engl J Med 2018, MURANO (NCBI E-utilities)
• FDA supplement approval letter, NDA 208573/S-004 and S-005 (VENCLEXTA), 2018
• ClinicalTrials.gov record for NCT02005471 (MURANO)
• NCI PDQ: Chronic Lymphocytic Leukemia Treatment (Health Professional Version)
• NCI SEER Stat Facts: Chronic Lymphocytic Leukemia

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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