Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors
Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating <i>KIT</i> 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...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/6/2983 |
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| author | William Shomali Jason Gotlib |
| author_facet | William Shomali Jason Gotlib |
| author_sort | William Shomali |
| collection | DOAJ |
| description | Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating <i>KIT</i> 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 <i>KIT</i> 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 <i>KIT</i> 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. |
| first_indexed | 2024-03-10T13:13:51Z |
| format | Article |
| id | doaj.art-ca550198ca044145b200727da32b877a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:13:51Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ca550198ca044145b200727da32b877a2023-11-21T10:35:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226298310.3390/ijms22062983Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT InhibitorsWilliam Shomali0Jason Gotlib1Division of Hematology, School of Medicine, Stanford Cancer Institute/Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-6555, USADivision of Hematology, School of Medicine, Stanford Cancer Institute/Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-6555, USASystemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating <i>KIT</i> 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 <i>KIT</i> 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 <i>KIT</i> 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.https://www.mdpi.com/1422-0067/22/6/2983systemic mastocytosis<i>KIT</i> D816VmidostaurinavapritinibIWG-MRT-ECNM |
| spellingShingle | William Shomali Jason Gotlib Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors International Journal of Molecular Sciences systemic mastocytosis <i>KIT</i> D816V midostaurin avapritinib IWG-MRT-ECNM |
| title | Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors |
| title_full | Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors |
| title_fullStr | Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors |
| title_full_unstemmed | Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors |
| title_short | Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors |
| title_sort | response criteria in advanced systemic mastocytosis evolution in the era of kit inhibitors |
| topic | systemic mastocytosis <i>KIT</i> D816V midostaurin avapritinib IWG-MRT-ECNM |
| url | https://www.mdpi.com/1422-0067/22/6/2983 |
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