FDA Approval: Ibrutinib (Imbruvica) for Leukemia

Two approvals, three months apart

Ibrutinib reached the market in stages, and the order matters.

On November 13, 2013, the FDA granted accelerated approval to Imbruvica for mantle cell lymphoma in people who had already had one prior therapy. That first approval was not for leukemia.

The leukemia approval came on February 12, 2014. It covered chronic lymphocytic leukemia, or CLL, in people who had received at least one prior therapy. A separate indication for CLL with a 17p deletion followed on July 28, 2014. Those approvals were accelerated, meaning the FDA cleared the drug on an early signal while confirmatory evidence was still being gathered.

What chronic lymphocytic leukemia is

CLL is a cancer of B lymphocytes, a type of white blood cell. NCI describes the disease as an accumulation of lymphocytes that look mature under a microscope but do not work properly. They build up in the blood, the bone marrow, and the lymph tissue.

The course is often slow. Many people are diagnosed by accident, when a routine blood count shows a high lymphocyte number and nothing feels wrong. Over time the disease can crowd the marrow. That leads to low red cells, low platelets, and a weakened immune system. NCI notes that bleeding and infection are major causes of death in CLL.

How it is diagnosed and staged

Diagnosis starts with a history and physical exam, including a check of lymph nodes in the neck, armpits and groin, and of the liver and spleen. A complete blood count with differential follows, plus a chemistry panel.

CLL does not use the usual stage 1 to 4 system. NCI presents two systems instead.

The Rai system runs from stage 0 to stage IV. Stage 0 is a high lymphocyte count alone. Stage I adds enlarged lymph nodes. Stage II adds an enlarged liver or spleen. Stage III adds anemia, with hemoglobin under 11 g/dL. Stage IV adds a low platelet count, under 100,000 per cubic millimeter.

The Binet system sorts people into clinical stage A, B or C, based on how many lymph node areas are involved and whether the marrow has begun to fail.

The 17p deletion named in that July 2014 indication is a missing piece of chromosome 17. It removes the TP53 gene and predicts a poor response to standard chemotherapy. That is why it was singled out. Finding it takes a specific test, which is one of many reasons biomarker testing is part of the workup.

How the drug works

Ibrutinib blocks Bruton's tyrosine kinase, usually shortened to BTK. BTK relays a survival signal from the B cell receptor on the surface of the cell. Blocking it removes that signal, and the malignant B cells stop being told to stay alive.

It is a capsule taken by mouth. The 2014 label sets the CLL dose at 420 mg once daily, and the mantle cell lymphoma dose at 560 mg once daily. Those are the 2014 label figures. Later labels and your own prescription may differ.

Those were the 2014 label amounts. Dosing has been revised since, and in any case your own haematology team decides what you take.

This is targeted therapy, not chemotherapy. It does not attack fast-dividing cells across the body.

The evidence behind the 2014 approval

Two studies supported it.

The first was small and uncontrolled: 48 people with previously treated CLL, median age 67, who had a median of four prior treatments. The overall response rate was 58.3%, with a 95% confidence interval of 43.2% to 72.4%. Every response was partial. Nobody had a complete response.

The second was a randomized phase 3 trial in 391 people, comparing ibrutinib with ofatumumab. Median progression-free survival was not reached in the ibrutinib group and was 8.1 months in the comparison group. The hazard ratio for progression or death was 0.22. For overall survival it was 0.43. A hazard ratio under 1 favors the ibrutinib group.

The label also lists real risks: bleeding, infections, low blood counts, kidney effects, and second cancers including skin cancers.

When to get checked

Most people with early CLL have no symptoms, so there is no screening test to ask for. What matters is not ignoring a pattern.

See a clinician if you notice any of these lasting more than two or three weeks:

• Lumps in the neck, armpit or groin that stay swollen and are not sore.
• Fatigue that rest does not fix.
• Drenching night sweats, or fevers with no infection to explain them.
• Weight loss of more than about 10% of your body weight without trying.
• Repeated infections, easy bruising, or bleeding gums.
• A feeling of fullness or discomfort under the left ribs, where the spleen sits.

A complete blood count is a cheap test and the usual first step. Our guide to leukemia explains what the numbers on that report mean.

The survival picture

SEER reports five-year relative survival for CLL at 90.2% for 2016 to 2022, with a median age at diagnosis of 71. About 22,760 new cases are expected in the United States in 2026.

That 90.2% is a group figure covering everyone diagnosed, at every stage, under the treatments of that period. It reflects how slow-moving much of this disease is. It does not describe any one person's future, and it does not account for the genetic features that shift an individual outlook.

What this approval cannot tell you

• The 2013 approval was for mantle cell lymphoma. The leukemia approval is the separate one from February 2014.
• Accelerated approval rests on an early measure, usually response rate. It is a bar the evidence cleared, not proof of longer life.
• Response in the small study was partial in every case. Partial means the disease shrank, not that it disappeared.
• Many people with early CLL do not need treatment at all. Watchful waiting is a real plan, not a delay.
• The CLL treatment landscape has changed substantially since 2014, so this page is a record of one approval rather than a guide to current options.

Sources

• FDA accelerated approval letter for IMBRUVICA (ibrutinib), NDA 205552, November 13, 2013
• FDA approval letter for IMBRUVICA in chronic lymphocytic leukemia, NDA 205552/S-001
• FDA prescribing information for IMBRUVICA (ibrutinib), 2014 CLL labeling
• Drugs@FDA overview: IMBRUVICA (ibrutinib), NDA 205552
• NCI PDQ: Chronic Lymphocytic Leukemia Treatment (Health Professional Version)
• SEER Cancer Stat Facts: Chronic Lymphocytic Leukemia

How this page was made

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

Cancer Explained is published by the National Cancer Information Foundation. It is not medical advice and does not suggest a test or treatment.

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