Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature

Abstract

Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 KIT mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 KIT mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia (n = 3), indolent SM (n = 3) and cutaneous mastocytosis (n = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months -400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease-. Absence of exon 17 KIT mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of KIT, and PR in one case. This later patient and all non-responders (n = 5) showed wild-type KIT. These results together with previous data from the literature support the relevance of the KIT mutational status in selecting SM patients who are candidates for imatinib therapy.

Keywords: KIT; imatinib; mast cell; mastocytosis; well-differentiated systemic mastocytosis.

Figure 1. Illustrating skin and bone marrow microscopic images obtained before and at month +12 of imatinib therapy in a patient with advanced WDSM who achieved CR (case #1)

(A–B) Macroscopic appearance of the skin and histological findings of skin biopsy (tryptase stain, 100x magnification) at diagnosis (A) and after imatinib therapy (B). (C–D) BM smears (toluidine blue stain, 100x magnification) at diagnosis (C) and after imatinib therapy (D). (E–F) BM sections (c-kit stain, 100x magnification) at diagnosis (E) and after imatinib therapy (F).

Figure 2. Effect of imatinib therapy on BM MC counts and sT levels in the 10 patients included in the present clinical trial

Vertical dotted lines indicate start of imatinib therapy, blue bars and grey dots represent the percentage of pathologic/aberrant BM MCs as assessed by flow cytometry and sT values, respectively, before and after imatinib therapy.

Figure 3. Effect of imatinib therapy on MC-mediator release associated symptoms in the 10 patients included in the present clinical trial

Symptomatic response was evaluated in each patient before starting imatinib and every 3 months thereafter using Likert-type scales obtained from specific questionnaires designed by the REMA, by which MC-mediator release symptoms (e.g. pruritus, purple lane; flushing, yellow lane; abdominal cramping, red lane; diarrhea, blue lane; and anaphylaxis, green lane) were graded as described in detail in the Methods section. The X-axis represents the different time-points at which the questionnaires were collected, while the Y-axis represents the overall score (i.e. the frequency score multiplied by the severity score) for each MC-mediator release-associated symptom.