Precision Medicine in Systemic Mastocytosis

Abstract

Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.

Mastocytosis and related entities: a practical roadmap

“…Other drugs such as masitinib, avapritinib, ripretinib and sarilumab are currently under investigation (43).…”

“…Therefore, cytoreductive therapy has a central role in this entity. The details are beyond the scope of this review but are discussed elsewhere (31,43). In highly aggressive AdvSM, hemapoetic stem cell transplantation should be considered.…”

KIT Mutations and Other Genetic Defects in Mastocytosis

“…7 These defects, usually associated with worse prognosis, 7 are best evidenced by next-generation sequencing (NGS). 8 Of note, 2 KIT-targeted tyrosine kinase inhibitors (KIT-TKIs), namely midostaurin (Rydapt), 9 and avapritinib (Ayvakit), 10 are now approved by FDA and European Mediines Agency (EMA) to treat AdvSM. In the era of such KIT-TKIs, the monitoring of the KIT D816V mutational burden has become one of the most potent markers to evaluate treatment response.…”