Imatinib in KIT-negative Systemic Mastocytosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations

Conditions
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Systemic Mastocytosis

Intervention / Treatment
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* Drug: Imatinib Mesylate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib mesylate<br>Imatinib mesylate 300 or 400 mg daily for 12 months. | Drug: Imatinib Mesylate<br>* In patients without B or C findings and without biological progression: 300 mg/24 h p.o during one year or until progression/unacceptable toxicity. In patients with B or C findings or biological progression: 300 mg/24 h p.o for two weeks and then 400 mg/24 h p.o for a total of one year of therapy, or until progression/unacceptable toxicity.<br>* Other names: STI571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. | The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients with B or C findings | 6 months | 
| To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. | The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients without B or C findings, and from those with B or C findings who show response at the intermediate check-point (after 6 months of therapy) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions. | Skin lesions are evaluated before and after therapy by macroscopic examination and skin biopsy. | 12 months | 
| To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms. | Clinical symptoms such as pruritus, flushing, gastrointestinal symptoms and anaphylaxis are assessed before and after therapy using a clinical questionnaire that includes the type, frequency and severity of each symptom. | 12 months | 
| To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies. | Organomegalies and adenomegalies are assessed before and after therapy by abdominal ultrasound. | 12 months | 
| To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations. | Bone alterations are assessed before and after therapy by X-ray survey. | 12 months | 
| To investigate changes after Imatinib Mesilate therapy in mast cell clonality. | Genetic abnormalities are assessed before and after therapy by sequencyng analysis of the c-kit gene and the HUMARA assay. | 12 months | 
| To determine the effect of Imatinib Mesylate therapy on serum tryptase levels. | Serum tryptase is measured before and after therapy. | 12 months | 
| To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life. | The psychological impact of the disease and the quality of life of patients are evaluated before and after therapy by the Dermatology Life Quality Index. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mast cell, Mastocytosis, Mast cell disease