#10 B-Cell Receptor Pathway Inhibitors

Overview

Chronic lymphocytic leukemia (CLL), a blood cancer that often occurs during or after middle age, is a cancer of the B cells, which are a major component of the immune system along with T cells. The cancer begins when too many blood stem cells become abnormal lymphocytes—leukemia cells—and not healthy white blood cells. This may soon cause infection and anemia. About 4,400 Americans die of the disease each year.

Standard treatment for CLL involves use of the chemotherapy, which can effectively control the disease until drug resistance arises, but chemotherapy has serious side effects, and sometimes causes death in older patients. For these reasons, new treatment approaches are needed for older CLL patients.

The last decade has seen dramatic advances in treatment outcomes for thousands of patients with CLL and other low-grade lymphomas, as new drugs have been developed that target CLL cancer cells with fewer side effects. These specially targeted therapies block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.

B-cells are the immune cells in the human body that are responsible for producing antibodies to fight infections and provide long-term immunity. However, like most cells in the body, B cells can become cancerous. B-cell lymphomas include both Hodgkin’s lymphomas and most non-Hodgkin’s lymphomas.

For CLL, there are now B-cell receptor pathway inhibitors that interfere with cancer cell division by focusing on proteins involved in signaling pathways. By effectively blocking signals that tell cancer cells to grow and divide uncontrollably, these targeted cancer therapies can help stop cancer progression and may induce “cancer suicide” through a process known as apoptosis, while preserving normal, healthy cells.

Ibrutinib, a first-in-class oral therapy, is a new agent that inhibits the B-cell receptor signaling complex that plays an important role in the survival of malignant B-cells. The drug targets Bruton’s tyrosine kinase, a protein essential for CLL-cell survival and proliferation. While it kills malignant B cells, ibrutinib has little effect on healthy T cells—unlike other CLL therapies. This leaves an important arm of the immune system largely intact, enabling patients to remain healthier during treatment.

Many CLL patients respond well to this novel B-cell receptor pathway inhibitor, which lacks many of the side effects of chemotherapy, and it frequently produces long-lasting remissions even in patients with high-risk genetic lesions. Results from a study published in the New England Journal of Medicine in 2013 reported an overall response rate  of 71% for patients with CLL who were treated with ibrutinib. At 26 months, the estimated progression-free survival rate was 75% and overall survival was 83%. Ibrutinib has also shown very promising results in the treatment of patients with other B-cell malignancies, including and mantle cell lymphoma (MCL), a rare and aggressive B-cell subtype of non-Hodgkin lymphoma.

With approval from the Food and Drug Administration (FDA) expected at the end of 2013, ibrutinib would be the first in a class of oral BTK inhibitors and one of the first medicines to file for FDA approval via the new Breakthrough Therapy Designation pathway, which is intended to expedite the development and review of drugs for serious or life-threatening conditions.

To follow soon after will be other much anticipated B-cell pathway inhibitors for leukemia, including syk (spleen tyrosine kinase) inhibitors and phosphoinositide-3 kinase (PI3K) inhibitors.

 

Where Are They Now

This drug is now FDA approved to treat three different kinds of rare blood cancer and is being studied in another 13 clinical trials as treatment for several other blood cancers. It’s the only therapy to receive three Breakthrough Therapy Designations by the FDA. In March 2016, the drug was approved for its fifth treatment indication and dubbed the ‘first-line’ treatment of chronic lymphocytic leukemia (CLL).

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