Response criteria for advanced systemic mastocytosis (AdvSM) have evolved along with the development of novel therapies, particularly those targeting the mast/stem cell growth factor receptor KIT. In spite of advances, response assessment in AdvSM remains complex and difficult due to several disease factors. One of the reasons is that, in most patients, AdvSM manifests as a multimutated disease affecting multiple cell lineages.
With such heterogeneity, treatment response may be variable in different clinical parameters, translating into significant challenges in SM clinical trials. For example, in the post hoc analysis of the global midostaurin registrational trial, the European Medicines Agency accepted the definition of overall response rate of the International Working Group criteria (ie, complete remission [CR] plus partial remission plus clinical improvement), whereas the US Food and Drug Administration (FDA) redefined it using CR plus partial remission only.
In an attempt to overcome such inconsistencies and other concerns of the regulatory authorities, the European Competence Network on Mastocytosis and the American Initiative on Mast Cell Diseases (ECNM-AIM) presented a refined version of response criteria for AdvSM at the European Competence Network on Mastocytosis 2020 Annual Meeting, Vienna, Austria.
“The proposed ECNM-AIM response criteria, born from successive prior versions, use a tiered approach to uncouple the effects of histopathologic, molecular, clinical, and symptom response on long-term outcomes,” Gotlib et al explained in the Journal of Allergy and Clinical Immunology: In Practice.
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The refined ECNM-AIM response criteria for AdvSM has 4 main tiers for the evaluation of treatment response and improvement of disease. In a hypothetical scenario of a trial to evaluate a novel therapeutic agent, is tier 1, which is focused on SM pathologic response (part 1A) and, if if an SM with an associated hematologic neoplasm (SM-AHN) is present, an AHN pathologic response (part 1B), would serve as the primary endpoint. The other tiers would serve as secondary endpoints as needed.
What Are the Potential Advantages of the Proposed ECNM-AIM Response Criteria?
With the proposed ECNM-AIM response criteria, adjudication of response after initiation of treatment is separated into 3 sequential tiers. Tier 1A evaluates mast cell infiltration of bone marrow, serum tryptase levels, and complete blood count, which are simple and objective markers that are easily interpreted by practicing physicians to determine treatment response.
Importantly, these criteria are applicable to all AdvSM patients with measurable disease burden, regardless of the presence of C-findings, which can be difficult to assess in the presence of AHN, treatment toxicity, or patient comorbidities, for example.
The separation of SM pathologic response from clinical response overcomes the potential confounding effect of an AHN, removes SM-related organ damage from the evaluation of the primary endpoint, and eliminates the concerns of lingering C-findings downgrading a CR or partial remission to stable disease.
Researchers Propose New Tiered Response Criteria for SM
In addition, the proposed ECNM-AIM response criteria allows an “a la carte” approach, ie, physicians could focus on response categories that reflect the particular needs of their patients. However, the authors recommend the reporting of all tiers for a more comprehensive evaluation of clinical benefit. So, in addition to the tier 1A SM pathologic response, which, in principle, would reflect the best treatment response, physicians are encouraged to report the AHN pathologic response when relevant (tier 1B), changes in the KIT D816V variant allele frequency (tier 2), changes in C-findings (tier 3), and symptoms/quality of life (tier 4).
A Concrete Example
William Shomali and Jason Gotlib from the Stanford Cancer Institute/Stanford University illustrated the potential advantage of using the newly proposed response criteria in a review article published in the International Journal of Molecular Sciences.
“If clearance of bone marrow mast cell infiltrates and normalization of the serum tryptase level were achieved (which would define a CR or CRh [CR with partial hematologic recovery] by pure pathologic response criteria), the presence of lingering organ damage findings would not downgrade the overall response. Such criteria simplify adjudication of response by relying solely on measures of mast cell burden without the need to integrate organ damage response(s) in the overall response assessment which can often be confounded by drug effects, co-morbid conditions, and/or by the AHN, if present.”
The newly proposed ECNM-AIM response criteria need to be evaluated in prospective future clinical trials.
Gotlib J, Schwaab J, Shomali W, et al. Proposed European Competence Network on Mastocytosis—American Initiative in Mast Cell Diseases (ECNM-AIM) response criteria in advanced systemic mastocytosis. J Allergy Clin Immunol Pract. 2022;10(8):2025-2038.e1. doi:10.1016/j.jaip.2022.05.034
Shomali W, Gotlib J. Response criteria in advanced systemic mastocytosis: evolution in the era of KIT inhibitors. Int J Mol Sci. 2021;22(6). doi:10.3390/ijms22062983