Mast cell leukemia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Nawal Muazam M.D.[2]
Overview
Medical Therapy
Therapeutic approaches are limited and consist of reducing the tumour burden and conservation of organ functions. To date, there is no approved standard therapy to treat SM with the exception of imatinib in D816V c-KIT negative patients.
Corticosteroids have been recommended as a short term use in combination with cytotoxic drugs. It could also be beneficial in some situations such as malabsorption, ascites, or anaphylaxis. Besides its role in alleviating MCMRS, corticosteroids decrease tissue mast cell burden by decreasing tissue stem cell factor [22] and this has been obviously demonstrated in our patient’s case with a dramatic tumour response and improvement of symptoms. Thus, corticosteroids could be used as an emergency treatment for ASM and MCL.
Preliminary studies suggested that Interferon-α (IFN) reduces the frequency of histamine related attacks, decrease BM infiltration by MCs, hepatomegaly, skin manifestations, and improve osteoporosis. However, no major responses were obtained and overall survival was not improved [23–25]. Relapses occurred frequently at the end of therapy and side effects were frequent. As a consequence the dropout rate is very high 25%. Its efficacy in MCL patients is very low or inexistent. 2-Chloro-deoxy-adenosine has a potential value in the treatment of ASM with symptomatic responses and improvement in mast cell variables. Complete responses are very rare [26, 27]. Cladribine has been used in rare cases of MCL with relatively small or no efficacy [21].
It is now well established that Imatinib does not have direct effect on the D816V KIT mutation, but it may affect other sporadic mutations [21, 28, 29]. Dasatinib demonstrates significant inhibitory activity against WT KIT as well as juxtamembrane domain mutant KIT [30, 31]. This activity has been proven in patients negative for D816V KIT [32]. Nilotinib displays also equipotent activity to Imatinib in D816V c-KIT negative patients and WT Kit cell line [33, 34].
Masatinib is a protein-tyrosine kinase inhibitor which, in vitro, potently and selectively inhibits the mutated form, in the juxtamembrane region, of the c-KIT receptor and the c-KIT wild-type receptor. It also inhibits the PDGF receptor and the mutated fibroblast growth factor receptor. Masatinib has been shown to be effective in patients with ISM or CM, not bearing the activating point mutations in the phospho transferase domain of c-KIT with an acceptable toxicity. Recently, Georgin-Lavialle et al. reported on a case of MCL with an exon 9 c-KIT mutation that was successfully treated by masatinib. Thus, this drug should be included in the therapeutic arsenal of mastocytosis patients especially D816V negative. An international randomized phase III in patients with CM and ISM independent of the c-KIT mutation status is ongoing. Finally, PKC412 (midostaurin) is a small molecule inhibitor of multiple type III receptor tyrosine kinases involved in hematopoiesis and leukemia, an inhibitor of all major isoforms of protein kinase C, the tyrosine kinase associated with the vascular endothelial growth factor receptor. It can also exert inhibitory activity on other mutated tyrosine kinases implicated in a variety of diseases, like KIT (systemic mast cell disease, gastrointestinal stromal tumors) PDGFR, or FGFR1. Midostaurin has shown strong inhibitory activity on neoplastic human MCs carrying the D816V c-KIT mutation in preclinical [35] and clinical settings [36]. Preliminary data of an ongoing phase II trial in patients with advanced systemic mastocytosis treated with 100 mg bid. Midostaurin revealed high overall response rates of 73%. An international phase II study in ASM and MCL is ongoing.