Imbruvica at ASH

When B-Cells Take a Wrong Turn Toward Cancer

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BTK is an enzyme in B cells that helps relay and process signals. Small molecules can inhibit BTK in B cell cancers.

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 (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.

Blocking Bruton’s Tyrosine Kinase (BTK)

What makes B cells take a "wrong turn" toward cancer? Researchers have many leads and potential targets, to match. But one target in particular has recently captured scientific interest, spurring therapeutic advances, with more than 50 related abstracts expected this year at the 2014 American Society of Hematology Annual Meeting (ASH).

The target is BTK, an enzyme that helps B cells receive signals from outside the cell. BTK influences B-cell development, or the series of steps by which B cells grow up into working immune cells.

Researchers discovered that blocking BTK with a small molecule reduced the ability of the cancerous cells to migrate, proliferate, and survive in vitro.

Based on preclinical success, human clinical trials were undertaken, with positive results. The US FDA has already designated the small molecule ibrutinib, which blocks BTK, as a breakthrough therapy, with a role in treating the following malignancies:

  • Mantle cell lymphoma
  • Chronic lymphocytic leukemia with 17p deletion, and
  • Waldenström’s macroglobulinemia.

Use of the agent is also being investigated in the treatment of other cancers, both alone and in combination with various therapies.

A brief overview of three relevant blood cancers follows.

What is Mantle Cell Lymphoma (MCL)?

MCL is an aggressive form of blood cancer that develops from B cells, a type of white blood cell (lymphocyte) that originates in the bone marrow. MCL results from a malignant transformation of a B-lymphocyte that is located in the outer edge of a lymph node follicle (the mantle zone). The abnormal B lymphocyte grows chaotically without the normal stops and safeguards, and the accumulated lymphoma cells form tumors in lymph nodes, which become enlarged.

The MCL cells can enter lymph circulation and the blood, and can spread to other lymph nodes or tissues, such as the bone marrow, liver and GI tract.

MCL is more prevalent among men than women, and the average age at diagnosis is the mid-60s.

Median overall survival rate (the middle number when the data from patients are arranged in a series) is three to four years. Unfortunately, due to its ability to grow aggressively and spread quickly, people with MCL often come to medical attention in the later stages of the disease.

MCL arises in B cells that are particularly dependent on the BTK signaling pathway for survival and expansion. Ibrutinib may benefit patients with MCL by blocking BTK and shrinking tumors.

What is Chronic Lymphocytic Leukemia (CLL)?

CLL is a slow-growing cancer that most commonly develops from B cells. CLL results from a malfunction in the normal life cycle of the cell, with the B lymphocytes dividing and reproducing themselves at an abnormal rate.

Cellular signaling pathways that normally control the cell do not function properly. Malignant B cells move to the supportive environment of the lymphatic system, such as bone marrow and the lymph nodes, becoming more numerous as they continue to multiply and survive.

The average age at diagnosis is 72, and median survival is eight to twelve years, but the prognosis varies with the stage and the presence of chromosomal abnormalities. More than 80 percent of patients with CLL have some type of chromosomal abnormality in their B cells, some of which are associated with poor response to conventional therapy.

The median predicted survival for CLL patients with the del 17p mutation is just two to three years and for patients with the 11q mutation is six-to-seven years, which is significantly less than nine-to-ten year survival for those without chromosomal abnormalities

Ibrutinib may benefit certain patients with CLL by blocking BTK, one component of a signaling pathway that promotes the survival and expansion of CLL B cells.

What is Waldenström’s Macroglobulinemia (WM)

WM is named after Swedish physician Jan Waldenström, who first described the disease’s clinical features in 1944. It’s a slow-growing and rare type of blood cancer that most commonly originates from B cells.

In certain malignant B cells there is a malfunction in the cellular signaling pathways that control cell growth and survival. Abnormal movement and adhesion cause the malignant B cells to congregate within the protective environment of the lymphatic system, where they are supported and continue to grow.

In WM, malignant B cells produce large amounts of an abnormal type of antibody protein called immunoglobulin M (IgM). Antibodies such as IgM normally help the body to fight infection, but excess IgM causes the blood to thicken and causes many of the symptoms of WM. Median age at diagnosis is 60-70 years, and median overall survival rate is 5-11 years.

B cells in WM are dependent on a signaling pathway that involves BTK. Ibrutinib, which blocks BTK, has been designated a breakthrough therapy by the FDA because it has shown benefit to patients with this rare disease.

Bottom Line

Bruton's tyrosine kinase is an important player in B-cell signaling and maturation. The US FDA has designated ibrutinib, an inhibitor of BTK, as a breakthrough therapy for MCL, CLL and WM, and clinical trials are ongoing.

Background Sources on Ibrutinib and Blood Cancer

Leukemia and Lymphoma Society. Mantle Cell Lymphoma Facts. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf. Accessed October 2014.

Cancer Research UK. What is mantle cell lymphoma. http://www.cancerresearchuk.org/cancer-help/type/non-hodgkins-lymphoma/about/types/mantle-cell-lymphoma. Accessed October 2014.

American Cancer Society. Leukemia--Chronic Lymphocytic. http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed July 2014.

CA: A Cancer Journal for Clinicians. Cancer Treatment and Survivorship Statistics, 2012. http://onlinelibrary.wiley.com/doi/10.3322/caac.21149/pdf. Accessed July 2014.

National Cancer Institute. “Chronic Lymphocytic Leukemia Treatment (PDQ®).” http://www.cancer.gov/cancertopics/pdq/treatment/CLL/healthprofessional/page1. Accessed September 2014.

Stilgenbauer S, Bullinger L, Lichter P, et al. Genetics of chronic lymphocytic leukemia: genomic aberrations and VH gene mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993-1007.

Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-6.

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