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Treatments for systemic mastocytosis: Latest updates from IACH
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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
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| 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.
- Radia DH. Systemic mastocytosis: Updates in clinical trials. Presented at: 7th Annual Meeting of the International Academy for Clinical Hematology; Sep 19-21, 2024; Paris, FR.
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