Available and emerging therapies for bona fide advanced sys temic mastocytosis and pri mary eosinophilic neoplasms

The his tor i cally poor prog no sis of patients with advanced sys temic mastocytosis (AdvSM) and pri mary eosin o philic neoplasms has shifted to increas ingly favor able out comes with the dis cov ery of druggable tar gets. The multikinase / KIT inhib i tor midostaurin and the highly selec tive KIT D816V inhib i tor avapritinib can elicit marked improve ments in measures of mast cell (MC) bur den as well as rever sion of MC - medi ated organ dam age (C - find ings) and dis ease symp toms. With avapritinib, the achieve ment of molec u lar remis sion of KIT D816V and improved survival compared with historical ther apy sug gests a poten tial to affect dis ease nat u ral his tory. BLU - 263 and bezuclastinib are KIT D816V inhib i tors currently being tested in tri als of AdvSM. In the new World Health Organization and International Consensus Classifi cations, the category of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions is inclusive of rearrangements involv ing PDGFRA, PDGFRB, FGFR1, JAK2, FLT3 , and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the poster children of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhib i tor pemigatinib, approved in August 2022, is a prom is ing ther apy in aggres sive FGFR1-driven diseases and high lights the role of such agents in bridg ing patients to allo ge neic trans plan ta tion. This review sum ma rizes the data for these approved and inves ti ga tional agents and discusses open ques tions and future pri or i ties regard ing the man agement of these rare dis eases.

Automated summary

With the discovery of druggable targets, the historically poor prognosis of patients with advanced systemic mastocytosis and primary eosinophilic neoplasms has improved. Drugs such as midostaurin and avapritinib have shown significant improvements in patients' conditions and can reverse organ damage and disease symptoms. Furthermore, other inhibitors are currently being tested, and some have already been approved.