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Treatments for systemic mastocytosis: Latest updates from IACH

By Dylan Barrett

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Oct 21, 2024

Learning objective: After reading this article, learners will be able to cite a new clinical development in systemic mastocytosis.


SM is a very rare, multifunctional, and multiorgan disorder and can be classified as non-advanced or advanced, with the overall life expectancy being linked to this classification.1 C-KIT D816V driver mutations are present in >90% of cases, as such KIT-targeting TKIs are promising therapeutic options for this patient population.1 During the 7th Annual Meeting of the IACH, Radia provided an overview of the current treatment landscape of SM, with a focus on advanced SM, and discussed treatment options such as KIT-targeting TKI inhibitors and allo-HSCT.1

Key learnings
Currently, two KIT-targeted agents, midostaurin and avapritinib, are approved for the treatment of SM, and avapritinib is the only agent approved for ISM. A further two agents, bezuclastinib and elenestinib, are being investigated in phase II clinical trials.  
The 3-year updated results from the multicenter, open-label, phase II PATHFINDER trial (NCT03580655) of avapritinib demonstrated a rapid and durable response rate of 75% across all advanced SM subtypes, with an ORR of 90% and 73% in treatment-naïve and previously treated patients, respectively. 
Preliminary data from the ongoing, open-label, multicenter, phase II APEX trial (NCT04996875) showed that bezuclastinib treatment resulted in a reduction of serum tryptase, bone marrow mast cell burden, and KIT D816V VAF in patients with advanced SM.
The majority of patients who progress after treatment with KIT inhibitors show presence of SM-AHN. This highlights the limitations of KIT monotherapy in a genetically complex disease. Several trials are evaluating the potential role of combination therapies, such as bezuclastinib plus HMA (APEX; NCT04996875), elenestinib plus HMA (AZURE; NCT05609942), and avapritinib plus decitabine (NCT06327685).
The EBMT Practice Harmonization and Guidelines provide an up-to-date framework to guide allo-HSCT in patients with advanced SM. In addition, with the advancements in KIT-targeting TKIs, treatment goals may evolve to focus on MRD negativity, treatment-free remission, combination therapies, preventing AHN progression to AML, and KIT inhibition in the peri-transplant setting.


Abbreviations: AHN, associated hematologic neoplasm; allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; EBMT, European Society for Blood and Marrow Transplantation; HMA, hypomethylating agent; IACH, International Academy for Clinical Hematology; ISM, indolent systemic mastocytosis; MRD, measurable residual disease; ORR, overall response rate; SM, systemic mastocytosis; TKI, tyrosine kinase inhibitor; VAF, variant allele frequency.

References

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