Imatinib in KIT-negative Systemic Mastocytosis
- Registration Number
- NCT01297777
- Lead Sponsor
- Hospital Virgen de la Salud
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 10
- Age older than 18 years.
- Diagnosis of systemic mastocytosis in the absence of c-kit mutation.
- ECOG ≤ 3.
- Signed informed consent.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Imatinib mesylate Imatinib Mesylate Imatinib mesylate 300 or 400 mg daily for 12 months.
- Primary Outcome Measures
Name Time Method To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. 12 months 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)
- Secondary Outcome Measures
Name Time Method To investigate changes after Imatinib Mesilate therapy in mast cell clonality. 12 months Genetic abnormalities are assessed before and after therapy by sequencyng analysis of the c-kit gene and the HUMARA assay.
To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life. 12 months 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.
To determine the effect of Imatinib Mesylate therapy on serum tryptase levels. 12 months Serum tryptase is measured before and after therapy.
To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions. 12 months Skin lesions are evaluated before and after therapy by macroscopic examination and skin biopsy.
To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms. 12 months 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.
To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies. 12 months Organomegalies and adenomegalies are assessed before and after therapy by abdominal ultrasound.
To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations. 12 months Bone alterations are assessed before and after therapy by X-ray survey.
Trial Locations
- Locations (1)
Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle
🇪🇸Toledo, Spain