Novel approaches in the treatment of systemic mastocytosis

Abstract

In the absence of curative options, therapy for aggressive forms of systemic mastocytosis (SM) has relied in the use of cytoreductive agents, mainly interferon-alpha (IFN-alpha) and cladribine. However, responses are transient and only occur in a subset of patients. Gain-of-function mutations at codon 816 of the KIT protooncogene lead to constitutively active Kit receptor molecules, which are central to the pathogenesis of SM. Recent advances in the understanding of the molecular underpinnings of SM have led to the development of small molecules targeting mutant Kit tyrosine kinase isoforms that significantly have widened the range of therapeutic options for patients with SM. Some of these promising agents, such as dasatinib, AMN107, and PKC412, currently are under investigation in clinical trials whereas, others are at different stages of preclinical development. In addition, monoclonal antibodies directed to neoplastic mast cell-restricted surface antigens constitute a viable option for the treatment of SM that warrants further investigation.

Systemic mastocytosis with acute myelomonocytic leukemia: a case report

“…In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established [14]. As clinically effective tyrosine kinase inhibitors that inhibit enzymatictype c-kit mutations are being developed [15], detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.…”

Systemic Mastocytosis: An Intriguing Disorder

“…Usually relief occurs many days or weeks after the introduction of a new drug, therefore the persistence of symptoms does not justify an earlier shift to others therapeutic schedules. As each new drug can trigger a hypersensitive reaction, one drug at a time should be introduced (Quintas-Cardama et al, 2006).…”

“…When first line fails, immunomodulating agents may be considered, such as prednisone, cyclosporine, methotrexate, and azathioprine (Quintas-Cardama et al, 2006). IFNα might be combined with prednisone, but it generally represents the first line agent for cytoreduction in ASM.…”

“…Omalizumab, a humanized murine antibody targeted to IgE, is now available as an experimental option (Quintas-Cardama et al, 2006). It seems to control MC activation syndrome also in patients resistant to conventional fist line therapy.…”

“…Gotlib et al reported a case of MCL associated with MDS/MPD who received a transient benefit from administration of midostaurin (Gotlib et al, 2005). More interestingly, midostaurin seems to exhibit a synergic activity with nilotinib (Quintas-Cardama et al, 2006), suggesting a more attracting role of these small molecules, as useful tools to combine in multidrug strategies in order to avoid the resistance to single agent approaches.…”