Lymphoma is the most common blood cancer. Lymphoma occurs when lymphocytes multiply uncontrollably. The body has two main types of lymphocytes that can develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells).
Waldenström's macroglobulinemia (also known as lymphoplasmacytic lymphoma or immunocytoma) is a rare, indolent (slow-growing) B-cell lymphoma that occurs in less than two percent of patients with non-Hodgkin lymphoma. There are about 1,500 new cases of Waldenström's each year. The disease is primarily found in the bone marrow, although lymph nodes and the spleen may be involved.
The disease, named after the Swedish oncologist Jan G. Waldenström, was first identified in 1944. The proliferation of B-cells interferes with the production of red blood cells, resulting in anemia. A characteristic of the disease is that the B-cells produce excess amounts of the immunoglobulin IgM. These high levels of IgM can cause a thickening of the blood, resulting in symptoms such as nosebleeds, headaches, dizziness, and blurring or loss of vision. Other symptoms may include tiredness, night sweats, headaches, pain or numbness in the extremities, and increased size of the liver, spleen, and lymph nodes.
Current treatment of WM includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide. Corticosteroids, such as Prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease. Recently, autologous bone marrow transplantation has been added to the available treatment options.
Bruton's tyrosine kinase (BTK), a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is required for B cell receptor signaling, plays a key role in B-cell maturation, and exhibits increased activation in a number of B-cell malignancies. BTK inhibitors are under investigation for the treatment of certain lymphomas. Prior to the present invention, BTK inhibitors had not been tested for treatment of WM.
CXCR4 is a chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12). CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 interaction is associated with several diseases, such as HIV, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, lupus and cancer. CXCR4's ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence.
There are known CXCR4 mutations associated with Warts, Hypogammaglobulinemia, Infection, and Myelokathexis (WHIM) syndrome (Hunter et al, ASCO 2012), a rare autosomal dominant genetic disorder that is caused by frame shift or nonsense mutations in the carboxyl-terminal cytoplasmic tail of CXCR4. In WHIM syndrome, the germ-line mutation causes a loss of the c-terminal tail of CXCR4, which is believed to impair receptor internalization, thereby prolonging signaling. Prior to the invention, there had been no known association between CXCR4 mutations and WM treatment.