Ibrutinib

Ibrutinib (Imbruvica) is a small molecule drug that binds permanently to a protein, Bruton's tyrosine kinase (BTK), that is important in B cells. It is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK).c-MET inhibitor: Cabozantinib (also VEGFR2). Ibrutinib (Imbruvica) is a small molecule drug that binds permanently to a protein, Bruton's tyrosine kinase (BTK), that is important in B cells. It is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. In January 2016 ibrutinib cost US$116,600 to $155,400 a year wholesale in the United States. Ibrutinib is used to treat chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia, and as a second-line treatment for mantle cell lymphoma, marginal zone lymphoma, and chronic graft vs host disease. It is a first line treatment in those with CLL who require treatment and are newly diagnosed. It may also be used in CLL that relapses. Both primary (inherent) and secondary (acquired) resistance has been reported in various lymphomas, including CLL and MCL. Resistance may arise due to mutations that impair the affinity of ibrutinib for BTK, or due to alterations in pathways downstream of BTK and may confer BCR signaling independence in resistant clones. Very common (>10% frequency) adverse effects include pneumonia, upper respiratory tract infection, sinusitis, skin infection, low neutrophil count, low platelet counts, headache, bleeding, bruising, diarrhea, vomiting, inflammation of mouth and lips, nausea, constipation, rash, joint pain, muscle spasms, musculoskeletal pain, fever, and edema. Common (1–10% frequency) adverse effects include sepsis, urinary tract infection, non-melanoma skin cancer (basal-cell carcinoma, squamous cell carcinoma), low leukocyte count, low lymphocyte count, interstitial lung disease, tumor lysis syndrome, high uric acid levels, dizziness, blurred vision, atrial fibrillation, subdural hematoma, nosebleeds, small bruises from broken blood vessels, high blood pressure, hives, and skin redness or blushing. Ibrutinib oral bioavailability is 3.9% in a fasting state, 8.4% in a fed state, and 15.9% after consumption of grapefruit juice. Ibrutinib has been reported to reduce chronic lymphocytic leukemia cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor (BCR). Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.