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.
Highlights
pure pathologic response (PPR) criteria include Complete response (CR)/CRh which requires resolution of bone marrow mast cell aggregates, a serum tryptase < 20 ng/mL, and either a full (CR) of partial (CRh) hematologic recovery; partial response (PR) which is defined as ≥50% reduction in bone marrow mast cells and serum tryptase level; progressive disease (PD), which is defined as transformation to acute myeloid leukemia (AML) or mast cell leukemia (MCL); and stable disease (SD), which does not meet criteria for CR/CRh, PR, or PD
KIT inhibition has transformed the treatment paradigm of Advanced SM (advSM) but has prompted a re-evaluation of how to tailor response criteria to best capture the clinical benefit of KIT-targeting drugs
Lessons learned from midostaurin and avapritinib clinical trials have led to modifications of the IWG criteria and an increasing recognition that more in-depth responses are feasible
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Systemic mastocytosis (SM) is a clonal, multisystem disease, driven by activating KIT mutations, most commonly D816V, that leads to accumulation of neoplastic mast cells in various organs [1]. This abnormal growth of mast cells results in organ damage in addition to mast cell-related mediator symptoms. The introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has resulted in a paradigm shift in the treatment of advSM and has prompted a re-evaluation how to optimize response criteria in order to best capture clinical benefit and long-term outcomes such as overall survival. They should be user-friendly and readily applicable in community practice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
