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Gleevec & Mastocytosis

- Nancy Gould, Former Research Committee Member
- Regis (Gigi) Park, Former Research Committee Chair

INTRODUCTION

Gleevec is a drug recently studied as a potential treatment for systemic mastocytosis. We will attempt to explain how Gleevec works and discuss studies reporting its use in the lab, on mast cells from mastocytosis patients, and in clinical use on patients with hypereosinophilic syndrome.

GLEEVEC – A TYROSINE KINASE INHIBITOR

Cells stay in touch with the environment outside their cell membrane largely through receptors, both on the surface and inside the cell. Molecules from outside the cell, referred to as ligands, attach to and stimulate these receptors triggering a series of events inside the cell that results in the cell’s performing one or more of its functions. Each kind of receptor “recognizes” one or a limited number of ligands, and a cell may have many thousands of copies of each kind of receptor on its outer membrane.

Growth factor receptors, when stimulated by their ligand, signal immature cells to multiply and mature, and prevent the death of mature cells. In some cases, they also signal the cell to perform some of its functions, such as releasing chemicals or producing proteins. The c-kit receptor on mast cells is a growth factor receptor in the tyrosine kinase family and its ligand is called stem cell factor.

When normal mast cells have no access to stem cell factor, they do not reproduce and cell death occurs as it should. However, the mast cells found in many adults with mastocytosis have a mutated gene that produces an abnormal c-kit receptor. The abnormality results in a constantly stimulated state and the failure of mast cells to die, even without stem cell factor. We will detail this c-kit mutation further in the next section.

Gleevec (also known as STI571, Glivec, and imatinib) is one of a family of drugs that interferes with the function of tyrosine kinase receptors. Thus, it is known as a tyrosine kinase inhibitor. As c-kit is in the family of tyrosine kinase receptors, researchers theorized that Gleevec might be used as a treatment for mastocytosis.

KIT MUTATIONS AND THEIR LOCATION ON THE KIT MOLECULE

In most people with systemic mastocytosis (SM), a mutation in the gene for the c-kit receptor causes a substitution of one amino acid (valine) for another (aspartate) at the 816th amino acid, causing this growth factor receptor to be constantly activated. This mutation, the Asp816Val activating mutation, is referred to as an “enzymatic pocket” type mutation.

In human gastro-intestinal stromal tumor, a disease in which Gleevec has been shown to produce dramatic tumor reduction and improved disease state, the location of a c-kit activating mutation is next to the cell membrane, just inside the cell, at the 560th amino acid. This portion of c-kit is known to be involved in regulating the activity of the molecule, preventing its activity when it is not stimulated by the presence of stem cell factor. A mutation in this area prevents the regulation of c-kit, allowing it to be active all the time even without stem cell factor-stimulation. This mutation, then, is said to be a “regulatory” type, or juxtamembrane (next to the membrane), mutation.

Cultured mast cells from a patient with mast cell leukemia, HMC-1 mast cells, have an enzymatic pocket-type mutation (816) and some of these cells also have a regulatory-type mutation (560).

EFFECT OF GLEEVEC ON THESE TYPES OF MUTATIONS

In order to determine whether Gleevec might be helpful in mastocytosis, it was applied in the laboratory to cultured mast cells that had these different kinds of mutations, as well as to normal, non-mutated mast cells. Several researchers have confirmed that in cultured mast cells with normal c-kit receptors, the addition of Gleevec to the culture results in the death of a portion of the mast cells. The number of mast cells dying depends on the amount of the drug applied to the culture.

Gleevec was tested on cultured mast cell leukemia mast cells, HMC-1 mast cells, with both a regulatory-type (560) mutation and an enzymatic pocket-type (816) mutation. The drug had no effect on these leukemic mast cells. Gleevec was then tested on HMC-1 cells with only the 560, regulatory-type mutation, and prevented the proliferation of those cells.

Then, Gleevec was tested on short term cultures of mast cells from the bone marrow of patients with mastocytosis whose affected mast cells had the 816 mutation and it did not kill those cells.

This work has been confirmed by several researchers and the conclusion we must draw is that Gleevec is not a good candidate drug for treating systemic mastocytosis on those patients with the 816 c-kit mutation.

SUCCESS OF GLEEVEC IN PATIENTS WITH HES WITH ELEVATED SERUM TRYPTASE

On a more positive note, researchers at the National Institutes of Health have recently identified a specific patient population for whom Gleevec may have a profound impact. These patients have hypereosinophilic syndrome (HES) which is characterized by the presence of idiopathic eosinophilia (an extremely high number of eosinophils in the blood for more than 6 months) and related organ dysfunction. They also meet the currently accepted criteria for the diagnosis of systemic mastocytosis by meeting three minor criteria – consistently elevated serum tryptase, the expression of CD25, and more than 25% of bone marrow mast cells that are atypical or spindle-shaped.

HES patients with elevated serum tryptase seem to respond very well to Gleevec. In the NIH study, the result of treatment with Gleevec was a decrease in eosinophilia, disappearance of the spindle-shaped mast cells, the normalization of serum tryptase levels, and resolution of myelofibrosis, a progressive disease of the bone marrow with a poor prognosis.

Of note, there are distinguishing features between HES patients with elevated tryptase and more traditionally recognized SM patients which suggest that the two conditions may have different underlying etiologies and which further makes a strong argument that the criteria for diagnosing SM may need revision.

This success with HES patients with elevated serum tryptase raises hope that continued work with other tyrosine kinase inhibitors may offer effective treatment for systemic mastocytosis patients in the near future. And, equally important, the work serves as further evidence that researchers must focus on the distinction of patient populations currently falling under the umbrella diagnosis of systemic mastocytosis.

Sources:

Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit; C Akin, K Brockow, C D Ambrosio, AS Kirshenbaum, Y Ma, BJ Longley, DD Metcalfe; Experimental Hematology 2003 Aug;31(8):686-692

Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms; Y Zermati, P De Sepulveda, F Feger, S Letard, et al; Oncogene 2003 Feb 6; 22(5):660-664

Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor; H. Joensuu, PJ Roberts, RM Sarlomo, B Druker, et al; New England Journal of Medicine 344(14):1052-56 (5 Apr 01)

Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness; Amy D Klion, Pierre Noel, Cem Akin, Melissa A Law, D Gary Gilliland, Jan Cools, Dean D Metcalfe, and Thomas B Nutman; Blood 15 June 2003;101(12):4660-4666

The authors wish to thank Dr. Cem Akin of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, for his review of this article.