Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

Abstract

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

Keywords: IWG-MRT-ECNM; KIT D816V; avapritinib; midostaurin; systemic mastocytosis.

Figure 1

Proposal for Tiered Response Criteria in Advanced Systemic Mastocytosis. After initiation of treatment, adjudication of response is separated into three sequential tiers. Evaluation commences with tier I: SM pathologic response (and if an SM with an associated hematologic neoplasm (SM-AHN) is present, concurrent pathologic assessment of the AHN component is undertaken; tier II: KIT D816V molecular response (evaluation of changes in cytogenetics and next generation sequencing mutation profile may also be undertaken at this step); and tier III: evaluation of clinical (organ damage) response using IWG or modified IWG criteria. Although not shown, a tier IV level of response evaluating symptoms (e.g., using the advanced systemic mastocytosis-symptom assessment form (AdvSM-SAF)) and other patient-reported outcome instruments evaluating quality of life may be considered. NGS: next-generation sequencing.