Imatinib in KIT-negative Systemic Mastocytosis

In vitro studies have proven that imatinib inhibits wild type Kit (wtKit) and suppresses proliferation of the HMC-1V560G cell line, while it is ineffective on inhibiting the growth of HMC-1V560G, D816V cells. Apart from wtKit, Kit molecules carrying mutations in the extracellular, transmembrane and juxtamembrane domains, such as V560G, F522C and K509I, remain sensitive to imatinib. In contrast, several experiments have provided compelling evidence regarding the resistance against the growth-inhibitory effects of imatinib on cells carrying the D816V KIT mutation. As a consequence, sensitive and specific methods should be used in order to avoid "false" KIT mutation-negative cases and, for that purpose, mainly in cases with low bone marrow mast cell numbers, mutational studies should be performed using highly purified bone marrow mast cells by means of Facs sorting systems better than whole bone marrow, unsorted mononuclear cell fraction or mononuclear cell fraction pre-enriched using magnetic beads conjugated with anti-CD25 monoclonal antibody. In the present study mutational studies were performed in all cases in purified bone marrow mast cells (purity \> 97%) using a FACSaria system (Becton-Dickinson Biosciences) as previously described. Patients without B or C findings according to the World Health Organization, and without features of biological progression of the disease receive oral Imatinib Mesylate 300 mg daily for up to 12 months or until clinical progression/unacceptable toxicity. Patients with B or C findings or biological progression initially receive oral Imatinib Mesylate 300 mg daily for two weeks; then, dose is increased up to 400 mg/day except in patients who develop hematological or any other dose-limiting toxicity. Biological progression is defined as the presence of at least one of the following features: i) increased serum tryptase levels \> 200 ng/mL, ii) diffuse bone sclerosis, iii) patchy sclerosis with osteolysis and increased risk of bone fracture or significant bone pain, and, iv) organomegalies or lymph node enlargement due to mastocytosis.