RESONATE: What the Leukemia Trial Found

The enzyme in the middle of the problem

Chronic lymphocytic leukemia is a cancer of B lymphocytes, a type of white blood cell. In CLL the marrow makes too many abnormal ones. They cannot fight infection well, and they crowd out healthy red cells, white cells, and platelets.

B cells stay alive by listening to a signal from their surface receptor. A relay enzyme called Bruton's tyrosine kinase, or BTK, carries that signal inward. Its label describes BTK as central to B-cell trafficking, movement, and sticking to tissue.

Ibrutinib blocks it. The drug forms a covalent bond with a cysteine in the BTK active site, which is a permanent attachment rather than a temporary block. Deprived of the signal, malignant B cells stop proliferating and lose their grip on the tissues sheltering them.

That mechanism was the theory. RESONATE tested it. Our page on targeted therapy covers this class of drug.

How the trial was set up

The ClinicalTrials.gov record, NCT01578707, describes a phase 3 study that opened in June 2012 and enrolled 391 people. It is now complete.

Participants had CLL or small lymphocytic lymphoma that had relapsed or stopped responding to earlier treatment. They were randomly assigned to daily ibrutinib by mouth or to ofatumumab, an antibody against CD20 given by infusion.

The primary endpoint was progression-free survival, judged by an independent review committee. Overall survival and overall response rate were secondary. The trial was open-label, meaning everyone knew which treatment they were getting.

What it found

At a median follow-up of 9.4 months, the ibrutinib group had not yet reached a median progression-free survival. Eighty-eight percent were progression-free at 6 months. The ofatumumab group had a median of 8.1 months.

The hazard ratio for progression or death was 0.22, with p less than 0.001.

Overall survival improved too, with a hazard ratio for death of 0.43 and p equal to 0.005. At 12 months, 90 percent of the ibrutinib group were alive against 81 percent.

The overall response rate was 42.6 percent against 4.1 percent. A further 20 percent of ibrutinib patients had a partial response with lymphocytosis, meaning a temporary rise in circulating lymphocytes as cells were flushed out of the tissues.

Similar effects appeared whether or not patients carried a deletion of chromosome 17p13.1, or had become resistant to purine analogues. That mattered. Those groups had had very poor options.

What the drug's label says now

Ibrutinib is sold as Imbruvica. Its label covers CLL and small lymphocytic lymphoma, CLL and SLL with 17p deletion, Waldenström's macroglobulinemia, and chronic graft versus host disease in adults and children aged 1 and older.

The warnings section is substantial, and it is what turns a good hazard ratio into a real-world decision.

Bleeding comes first. The label reports fatal bleeding events. Major hemorrhage occurred in 4.2 percent of 2,838 patients across 27 trials, with fatalities in 0.4 percent. Bleeding of any grade, including bruising and pinpoint spots, occurred in 39 percent. Taking a blood thinner or antiplatelet drug alongside raises that risk.

Heart rhythm problems come next. Grade 3 or higher atrial fibrillation and atrial flutter were reported in 3.7 percent of 4,896 patients, and severe heart failure in 1.3 percent. Risk was higher in people with high blood pressure, diabetes, previous arrhythmias, or an acute infection.

The label also flags infections, high blood pressure, low blood counts checked monthly, second cancers including skin cancers, liver injury, and tumor lysis syndrome.

When to call the team during treatment

The label ties monitoring to specific signs. Anyone on this drug should report:

• Bleeding that will not stop, blood in stool or urine, or coughing up blood
• A sudden severe headache, confusion, or weakness on one side, which can signal bleeding in the brain
• Palpitations, lightheadedness, fainting, chest pain, or new breathlessness
• Fever, which needs same-day assessment given the infection risk
• Home blood pressure readings above the target the team has set

Complete blood counts are checked monthly, and liver function throughout.

Where CLL sits in the wider picture

For 2026 the American Cancer Society forecasts 22,760 new CLL cases in the United States and 4,350 deaths; SEER hosts the forecast rather than producing it. The survival figure is SEER's own: 90.2 percent at five years for cases from 2016 to 2022. About 0.6 percent of people are diagnosed at some point in life.

Not everyone with CLL is treated. NCI lists watchful waiting as a standard option, meaning close monitoring with no treatment until signs or symptoms appear or change.

CLL often causes nothing early and is found on a routine blood test. NCI says to check with a doctor about painless swelling of lymph nodes in the neck, underarm, stomach, or groin; weakness or tiredness; pain or fullness below the ribs; fever and infection; easy bruising or bleeding; petechiae, which are flat pinpoint dark-red spots under the skin; unexplained weight loss; and drenching night sweats. Our page on leukemia covers the four main types.

What this trial cannot tell you

Median follow-up was 9.4 months. Median progression-free survival in the ibrutinib arm had not been reached, so how long the benefit lasts was simply unknown at publication.

The published abstract gives hazard ratios without confidence intervals. From that source alone, the precision of those estimates cannot be stated.

The comparator also shapes the result. Ofatumumab was a modest option even in 2014, so beating it is a lower bar than beating today's alternatives. The open-label design leaves room for bias in anything judged subjectively.

And the field moved. Second-generation BTK inhibitors have since been developed with better tolerability, and combinations have changed first-line care. A landmark trial marks where a field turned, not where it ended up. Our page on clinical trial vs standard treatment explains how that transition works.

Sources

• Byrd JC and colleagues, Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia, N Engl J Med 2014 — https://pubmed.ncbi.nlm.nih.gov/24881631/
• ClinicalTrials.gov, RESONATE (NCT01578707) — https://clinicaltrials.gov/study/NCT01578707
• DailyMed, IMBRUVICA (ibrutinib) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dfd0279-ff17-4ea9-89be-9803c71bab44
• NCI PDQ, Chronic Lymphocytic Leukemia Treatment (Patient Version) — https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq
• SEER Cancer Stat Facts, Chronic Lymphocytic Leukemia — https://seer.cancer.gov/statfacts/html/clyl.html

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.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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