Avapritinib (Ayvakit™) shows marked improvements in patients with advanced systemic mastocytosis (SM), which has been demonstrated in several studies. However, multiple challenges and questions remain, as recently discussed by experts in an article published in Blood.

The authors emphasized the need to establish adequate standards for molecular monitoring of KIT D816V and the concept of minimal residual disease in advanced SM. Regarding the last, they highlighted 3 open questions:

  • Whether achieving molecular remission translates into prolonged progression-free survival and overall survival;
  • Whether the benefits of minimal residual disease negativity apply only to advanced SM subtypes without an associated hematologic neoplasm (SM-AHN) or the presence of a multimutated landscape beyond KIT
    D816V; and
  • Whether molecular remissions permit time-limited treatment and the possibility of durable treatment-free remission.

Clinical progression and transformation of SM-AHN to secondary acute myeloid leukemia remains a major therapeutic challenge. The combination of avapritinib with AHN-directed therapy seems a potential approach but requires further investigation to determine the impact of AHN remission on progression-free survival and overall survival.

Read more about SM treatments

“The hybrid nature of SM-AHN makes it particularly amenable to the study of its clonal architecture under the pressure of KIT inhibition, with or without AHN-directed therapy,” the experts wrote. “Single cell sequencing may provide insights into the molecular ontogeny of the SM and AHN disease compartments and how they co-evolve during response and progression on avapritinib or other KIT D816V inhibitors, including BLU-263 and bezuclastinib.”

In addition, the experts believe that an alternating sequential treatment is preferred over concurrent avapritinib plus HMA treatment due to concerns for intracranial bleeding with higher-grade thrombocytopenia. Alternatively, BLU-263, a KIT D816V inhibitor that is equipotent to avapritinib in vitro, may allow for the study of concurrent and sequential combination strategies with AHN-directed therapies if intracranial bleedings are not identified as a safety signal in ongoing or future studies. It may also provide an opportunity for triplet regimens for high-risk SM-AHN.

Avapritinib Shows Potential for Treating KIT-Negative Advanced SM

A reasonable therapeutic option for SM-AHN is allogeneic hematopoietic stem cell transplantation, particularly in patients with high-risk features within the AHN component. The experts suggest that using avapritinib for debulking the SM component could be a useful, though not yet tested, pretransplant strategy.

Currently, the clinical experience with avapritinib before and after transplant to prevent or treat relapse is limited. However, the pretransplant use of KIT inhibitors could be advantageous, as many patients undergo transplantation without being in complete remission and thus are at increased risk of relapse.


Gotlib J, Reiter A, DeAngelo DJ. Avapritinib for advanced systemic mastocytosis. Blood. 2022;140(15):1667-1673. doi:10.1182/blood.2021014612