Ibrutinib (Imbruvica) - Now Approved First Line for CLL


Chemotherapy kills or slows the growth of cancer cells. Immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer. The combination of the two, or chemo-immunotherapy, is the mainstay or first-choice for therapy for blood cancers like mantle cell lymphoma and chronic lymphocytic leukemia, or CLL.

Small molecules like ibrutinib are staking out their own turf, however, including first-choice treatment for particular patients certain CLL.

Ibrutinib is also indicated for a little-known disease that makes a lot of antibodies of the IgM variety. Early in 2015, the FDA expanded approved uses of ibrutinib to include Waldenstrom Macroglobulinemia, or WM -- a type of non-Hodgkin lymphoma diagnosed in only about 1,000 to 1,500 Americans each year. WM typically surfaces in older adults, ages 60 to 70. It's a rare form of cancer that begins in the body’s immune system—specifically in the B lymphocytes, or B-cells.

Ibrutinib Quashes Signals Some Cancer Cells Rely On

Lymphocytes are in the blood and are a kind of white blood cell. There are three kinds of lymphocytes: B cells, T cells and Natural Killer cells. B cells mature and develop in a series of steps, from early stages in the bone marrow to mature stages in lymph nodes.

Throughout these stages, B cells rely on cellular signaling, which is the communication process that governs basic cell activity and coordinates cell action.

Different proteins or protein complexes, such as enzymes, are involved in the cell signaling, and may cause certain changes within the cell.

Bruton’s Tyrosine Kinase, or BTK, is an example of an enzyme that regulates cell signaling. Ibrutinib is a small molecule that blocks BTK. By blocking this enzyme, ibrutinib interferes with a signaling pathway that certain cancer cells rely on.

How Ibrutinib is Used

Ibrutinib is a prescription medication with a role in treating people with the following malignancies:

  • Chronic lymphocytic leukemia (CLL)
    The National Comprehensive Cancer Network (NCCN) recommends ibrutinib as a first-choice treatment option for frail CLL patients with significant other health conditions, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant other health conditions.
  • Waldenström's macroglobulinemia (WM)
  • Mantle cell lymphoma (MCL) who have received at least one prior treatment

It is not yet known if ibrutinib is safe and effective in children.

According to clinicians interviewed by HemOnc Today, ibrutinib is one of the most effective and least toxic therapies yet developed for CLL.

Ibrutinib for Waldenstrom's Macroglobulinemia

WM occurs when the body makes too many abnormal B cells that crowd out healthy blood cells in the bone marrow. The abnormal B cells release excess IgM antibodies into the blood, and this can cause a variety of adverse symptoms including excess bleeding, problems with vision and with the nervous system.

People who are prescribed ibrutinib typically have experienced WM symptoms such as low blood counts, clumping of proteins in the blood, nerve pain, or other immune symptoms.

The FDA based its approval of ibrutinib for WM on a clinical study of 63 previously treated participants. All study participants received a daily orally administered dose of the medication until the disease progressed or side effects became intolerable.

Results showed 62 percent of participants had their cancer shrink after treatment, and the duration of response (at the time of the study) ranged from about 3 months to approximately 19 months.

Those patients who responded had a reduction in IgM levels while taking ibrutinib.

This new use was approved more than two months ahead of schedule by the FDA.

Side Effects

Ibrutinib is generally very well tolerated with a very acceptable side-effect profile in all patient groups. However, as with any medication, the decision to treat is informed by what is known about the potential benefits and risks. The most common side effects associated with the drug are low blood platelet counts (thrombocytopenia), a decrease in infection-fighting white blood cells (neutropenia), diarrhea, low red blood cell counts (anemia), lack of energy (fatigue), musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash.

Future Directions

Ibrutinib combinations with other targeted therapies such as PI3Kδ inhibitors and the anti-BCL-2 molecule, Venetoclax, are of interest. Some studies are planned and some are in the works. Such combinations could potentially offer a solution to ibrutinib resistance, but it remains to be seen whether inconspicuous side-effect profiles of individual drugs will remain modest when combinations are used.


Ibrutinib Prescribing Information. http://www.imbruvica.com/docs/librariesprovider3/default-document-library/prescribing_information.pdf?sfvrsn=2 Accessed January 2015.

FDA News. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. Accessed January 2015.

Tucker DL, Rule SA. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. Therapeutics and Clinical Risk Management. 2015;11:979-990.

Updated November 24, 2015.

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