Imatinib in KIT-negative Systemic Mastocytosis
Imatinib in KIT-negative Systemic Mastocytosis
The aim of this study is to evaluate the efficacy in terms of clinical and biological
 response rates of Imatinib Mesylate therapy in patients with systemic mastocytosis 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.
Inclusion Criteria:

 -  Age older than 18 years.

 -  Diagnosis of systemic mastocytosis in the absence of c-kit mutation.

 -  ECOG ≤ 3.

 -  Signed informed consent.

 Exclusion Criteria:

 -  Previous therapy with a tyrosin kinase inhibitor.

 -  Positive antibodies against HIV or active viral hepatitis.

 -  Impaired liver function (total bilirubin ≥ 2.0 mg/dl, AST or ALT > 3 x upper limit of
 normal).

 -  Impaired renal function (≥ 2.0 mg/dL).

 -  Grade III-IV cytopenias not related to mastocytosis.

 -  Severe cardiopathy (grade III/IV of NYHA, or left ventricular ejection fraction <
 50%).

 -  Pregnancy or breastfeeding.

 -  Female patients who do not use contraceptive methods.