Gleevec is a drug that has a very narrow mode of action, and was developed for a disease other than MCAS, so how does it work in MCAS? This quote is from a presentation by Dr Afrin and explains what is known about this question "I suspect the reason imatinib can work in some patients with the
D816V mutation is that most of these patients have multiple mutations. We know imatinib can stabilize some of the other mutations, i.e., it doesn’t focus just on the D816V mutation. We don’t exactly know the molecular mechanism yet of how it stabilizes the other mutations or which ones. The fundamental issue with mutations is that although KIT is ordinarily quiescent until it gets activated by stem cell factor, these mutations lead to constitutive activation of KIT. Once KIT is always on, you’ve got to find a way to stabilize it."
KIT is a protein that is expressed on the surface of some types of cells, and once activated by SCF (Stem Cell Factor), it activates pathways in the cell that regulate cellular growth, division, survival, and movement. Somatic mutations in a gene are mutations that are acquired since birth, not ones that are inherited. Somatic mutations in KIT can create a signalling protein in the cell that does not need the KIT receptor on the cell's surface to be activated- the mutated protein results in a pathway that is constantly turned "on". Cells that express KIT (also called CD 117) on their surface include mast cells, melanocytes (cells that produce melanin, then most common pigment of eyes, hair, and skin), reproductive cells (germ cells), and cells in the GI tract called interstitial cells of Cajal (ICCs). Interestingly ICCs are involved in peristalsis, the movement of food through the GI tract, and many people with MCAS have problems with this.
Whether or not Gleevec actually counts as a chemotherapy drug is a semantic debate. Chemotherapy drugs are usually thought to be drugs that kill cells, while Gleevec is an example of a drug that works via targeting specific proteins in the cell rather than killing it- called targeted therapy. It was developed to treat certain forms of cancer which is part of why it is associated with chemotherapy. It does appear to be safer than the older, non-targeted chemo agents that affected large amounts of body systems and have many side effects. As a relatively new drug I do not think that the safety profile has been fully understood yet. Similar drugs include Dasatinib and Sunitinib (which targets and inhibits vascular endothelial growth factor).
Sources and Further Reading:
Gleevec: the Breakthrough in Cancer Treatment
How Gleevec Works
Gleevec information sheet from Novartis
Clinical Pharmacokinetics of Imatinib Mesylate
Patients Taking Imatinib for CML Have Similar Risk of Death as General Population
Endocrine side effects of broad-acting kinase inhibitors
Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase
"IM is associated with toxicity, though most of the adverse effects attributed occur within the first 2 years of starting therapy and some reverse with continued treatment at the same dose. Toxicity appears mild to moderate in most instances and appears easily manageable and potentially reversible. Some patients may experience lethargy and develop different types of rashes; others gain weight from fluid retention, especially infraorbital edema but occasionally much more generalized, which responds in some cases to diuretics. Other effects include bone pain, which can sometimes be debilitating. Liver chemistry can be abnormal, and this may, on rare occasions, progress to liver failure. Rare incidences of prolongation of the QTc interval on the electrocardiograph have been reported. A small proportion of patients in CP who start IM at 400 mg/day experience cytopenias within the first year of therapy. They typically develop neutropenia and/or thrombocytopenia and sometimes anemia."
Case Histories of Severe Depression With Imatinib and Dasatinib
In Mast Cell Disease:
This is a presentation given by Dr Afrin in which he discusses a number of cases in which Gleevec was given and resulted in dramatic improvement. The presentation itself if very long (153 pages) and covers a lot of ground, but the case histories are interesting.
Patients with systemic mastocytosis received imatinib mesylate orally at a dose of 400 mg once daily for 3 to 6 months. Low doses of prednisone were added during the first 2 weeks. Endpoints were reductions in serum tryptase, urinary N-methylhistamine excretion, skin lesions, the number of mast cells in bone marrow sections, hepatomegaly and/or splenomegaly, and symptoms.
bcr-abl-Induced Cell Lines Can Switch From Mast Cell to Erythroid or Myeloid Differentiation In Vitro
" Engraftment of mice with bone marrow cells infected with a bcr-ab1 retrovirus has been shown to elicit multiple hematopoietic disorders, including a clonal but nontransplantable hyperproliferation
of erythroid and/or mast cells. Culture of spleen and bone marrow cells from such mice usually yielded mast cell lines, even when erythroid disease dominated the primary animal. The mast cells, which carried the same proviral insert as the primary disease, generally grew slowly and were neither transplantable nor clonogenic in agar until they had been cultured for several months. Unexpectedly, several bcr-ab/-induced lines switched in vitro from mast cell to megakaryocytic and/or erythroid character, and one became myeloid. The dramatic phenotypic shifts seem likely to involve changes occurring within progenitor cells maintaining the clone, rather than mutation of mature mast cells. The variant lines exhibited substantial spontaneous differentiation, despite being readily ransplantable and therefore fully transformed. The production of hematopoietic growth factors by the mast cell lines and their phenotypic variants may implicate an autocrine loop in their evolution."
Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia.
Complete Response After Imatinib Mesylate Therapy in a Patient With Well-Differentiated Systemic Mastocytosis
Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion.