Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the effect of Imatinib Mesylate on clinical mastocytosis-related features: skin lesions, mast-cell related symptoms (pruritus, flushing, gastrointestinal symptoms, anaphylaxis), organomegalies/adenopathies and bone alterations.
Clinical parameters are evaluated before and after therapy by macroscopic and histological skin examination, the record of frequency and severity of mast cell-mediators release symptoms, abdominal ultrasonography and x-ray survey.
Luis Escribano, MD, PhD
Instituto de Estudios de Mastocitosis de Castilla La Mancha
Spain: Ministry of Health