<p>Novel approaches to treating advanced systemic mastocytosis</p>

Abstract

Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KIT D816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KIT D816V . Midostaurin, a broad spectrum TKI with activity against KIT D816V , has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KIT D816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KIT D816V . Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KIT D816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.

Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors

“…Awareness of cognitive changes specific to avapritinib may help the oncologist rule out other etiologies. In light of the long half-life of avapritinib (~25 hours) [37], dose interruption for 1-2 weeks rather than dose reduction may be preferred for AE management. We recommend dose interruption with or without subsequent reduction at the first sign of any cognitive impairment, including grade 1 events.…”

Acute aleukemic mast cell leukemia: Report of a case and review of the literature

“…SRF2, ASXL1, RUNX1, TET2, CBL, K/N-RAS , and EZH2, which have been shown to lead to poorer outcomes [ 19 , 20 ]. In contrast with other types of SM, only 40–67% of MCL cases carry the typical KIT D816V mutation [ 3 , 13 , [19] , [20] , [21] ]. A proportion of these “negative” cases may carry a codon 816 KIT mutation other than D816V or a non-codon 816 KIT mutation[ 3 , 19 ].…”

“…While the goal of therapy in indolent variants of SM has traditionally been symptomatic relief by using e.g. antihistamines, mast cell stabilizers, leukotriene inhibitors, proton pump inhibitors, and NSAIDs, in MCL (and also in aggressive systemic mastocytosis) reversal of C-findings and their organ damage-related symptomatology represents the current treatment strategy [21] . Treatment options of MCL cases range from tyrosine kinase inhibitors (TKI), chemotherapy, and allogeneic stem cell transplant [ 21 , 22 ].…”

Systemic Mastocytosis: Molecular Landscape and Implications for Treatment

“…However, the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the prognosis and the outcome of patients with AdvSM. 70 Several TKIs, such as imatinib, nilotinib, and masitinib, have shown activity against wild-type KIT. They belong to type II TKI inhibitors, so they recognize only the inactive conformation of the receptor and stabilize it.…”

“…Despite the great hurdle represented by the rarity of AdvSM patients, the tyrosine kinase inhibitor midostaurin has recently been approved based on the results of phase 2 clinical trial that lasted almost 10 years. 11 Other investigational agents, like avapritinib and ripretinib, are being evaluated. In addition, several additional compounds with the same or even different targets have been tested at the preclinical level.…”