Management of Advanced Systemic Mastocytosis and Associated Myeloid Neoplasms.

Advanced systemic mastocytosis (AdvSM) is a heterogeneous group of disorders characterized by neoplastic mast cell-related organ damage and frequently associated with a myeloid neoplasm. The 3 clinical entities that comprise AdvSM are aggressive SM (ASM), SM-associated hematologic neoplasm, and mast cell leukemia. A gain-of-function KIT D816 V mutation is the primary oncogenic driver found in about 90% of all patients with AdvSM. Midostaurin, an oral multikinase inhibitor with activity against KIT D816V, and avapritinib, an oral selective KIT D816V inhibitor are approved for AdvSM.

Update on diagnostic approaches and therapeutic strategies in systemic mastocytosis.

Systemic mastocytosis is a rare disease which is being better recognized and managed. While the vast majority of patients have indolent disease with variable symptom burden, a small proportion evolve or present with aggressive disease. This may be due to increases in mast cell burden (leukemic, associated with tumour masses) or more commonly due to the presence of an additional hematologic neoplasm (SM-AHN). These patients with advanced systemic mastocytosis have poor outcome; however, recent advances in diagnosis, molecular genetics and treatment have changed the prognostic landscape for this group of patients. In this review we address the most topical questions related to diagnostics, classification, new disease entities, treatment and multiparameter prognostic scoring systems.

Standards of Pathology in the Diagnosis of Systemic Mastocytosis: Recommendations of the EU-US Cooperative Group.

Pathology plays a central role in the diagnosis of systemic mastocytosis (SM), its delineation from other neoplasms and reactive conditions, and in monitoring of SM under therapy. The morphologic hallmark of SM is the accumulation of spindle-shaped, hypogranulated mast cells (MCs) in bone marrow (BM) and other extracutaneous tissues. Four of the 5 World Health Organization-defined diagnostic criteria (ie, compact MC aggregates [=major criterion]; atypical MC morphology; activating KIT point mutations; aberrant expression of CD25 and/or CD2 and/or CD30 in MCs [=minor criteria]) can be addressed by the pathologist. The final classification of SM variants as either BM mastocytosis, indolent SM, smoldering SM, aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or MC leukemia (MCL) has important prognostic significance and requires the integration of certain morphological, clinical, radiological, and biochemical data, referred to as B- and C-findings. Substantial diagnostic challenges may be posed to the pathologist and clinician especially in the so-called advanced SM variants, that is, ASM, MCL, and SM-AHN. In this article, updated recommendations of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM, presented during the year 2020 Working Conference held in September in Vienna, are reported.

Comprehensive Clinicopathologic and Molecular Analysis of Mast Cell Leukemia With Associated Hematologic Neoplasm: A Report and In-Depth Study of 5 Cases.

Mast cell leukemia with associated hematologic neoplasm (MCL-AHN) is a rare and highly aggressive entity that remains understudied due to the paucity of cases. We present a case of a 45-year-old man who was concurrently diagnosed with mast cell leukemia and acute myeloid leukemia. We identified four additional patients who had MCL-AHN in our institution and performed whole-exome sequencing of all available tumors. Our series revealed a novel and identical NR2F6 variant shared among two of the patients. This case series and sequencing results demonstrate the importance of fully characterizing rare tumors that are resistant to treatment.

Avapritinib for Systemic Mastocytosis.

INTRODUCTION: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven in ≈95% of cases by activating KIT mutations, usually D816V. SM can be indolent (ISM), smoldering (SSM) and advanced (AdvSM), the latter characterized by organ damage resulting from infiltrating neoplastic mast cells. The vast majority of cases are indolent, with near-normal life expectancy, although symptoms can be severe. AdvSM, comprising aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia, however, carries a poor prognosis. Avapritinib is a highly potent and selective inhibitor of mutant KIT. AREAS COVERED: We provide an overview of SM, including the current therapeutic landscape, and discuss avapritinib in detail: its chemistry and discovery, pharmacodynamic and pharmacokinetic data, current approval status and safety and efficacy profiles in both advanced and non-advanced SM. EXPERT OPINION: With a response rate of 75% amongst evaluable patients with AdvSM and marked reductions observed in measures of mast cell and disease burden, avapritinib stands out as a highly effective targeted therapy for this mutant KIT-driven disease. Cognitive impairment may occur, and intracranial hemorrhage has been reported, particularly in association with severe thrombocytopenia. Early results in patients with ISM/SSM are encouraging. Avapritinib is now approved in the US for AdvSM.