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.

Keywords: KIT; genetics; precision medicine; systemic mastocytosis; tyrosine kinase inhibitor.

Figure 1

Diagnostic workup of a patient with suspected mastocytosis. The diagnostic workup of a patient with suspected mastocytosis should start with personal medication history, physical examination, counseling about triggers that may increase MCs activation, and collection of signs and symptoms. A multidisciplinary approach is useful. Laboratory tests include CBC with manual differential, serum tryptase level, BM biopsy with IHC for detection of CD25, and flow cytometry for MCs CD25 and in selected cases of CD30 expression if IHC is not available [21]. Molecular testing for KIT D816V mutation (in BM, PB, or other lesions) should be performed, as well as for FIP1L1-PDGFRA if eosinophilia is present. If available, the NGS test may be assessed. Major and minor criteria should be reached. After the identification of SM, B and C findings should be defined for the correct identification of SM variants. Abbreviations: MCs, mast cells; CBC, complete blood count; BM, bone marrow; IHC, immunohistochemistry; PB, peripheral blood; SM, systemic mastocytosis; NGS, next generation sequencing; MIS, mastocytosis in the skin; SM-AHN, systemic mastocytosis associated with a hematological neoplasm; ISM, indolent systemic mastocytosis; SSM, smoldering systemic mastocytosis; ASM, aggressive systemic mastocytosis; MCL, mast cell leukemia.

Figure 2

Bone marrow histology of patient affected by SM. Panel (A): Giemsa; 40×: perivascular spindle-shaped mast cells with abnormal cytologic features (spindling and hypogranularity). Panel (B): CD117; 40×: in tissue sections, an immunohistochemical stain can be used for identification of mastcells. Panel (C): immunostaining with CD25 shows an atypical immunophenotype of mast cells with membrane reactivity.

Figure 3

KIT structure and related activation pathway in mastocytosis. The proto-oncogene KIT encodes a type III tyrosine-kinase (TK) receptor, consisting of an extracellular domain (ECD) with five immunoglobulin-like motives, that includes the stem cell factor (SCF) binding site, a transmembrane domain (TMD), a juxta membrane domain (JMD), and two catalytic tyrosine kinase domains with ATP and phosphotransferase domain (PTD) binding site, separated by a kinase insert [42,44]. In normal conditions, the SCF ties the KIT binding site leading to receptor dimerization, autophosphorylation and kinase domain activation. Consequentially, it triggers a cascade of multimolecular phosphorylation resulting in different signal transduction pathways, such as the Janus kinase (JAK) and the signal transducers and activators of transcription (STAT), the phosphatidylinositol triphosphate kinase (PI3K), the rat sarcoma (RAS), and extracellular signal-regulated kinase (ERK) pathway [42,47,48,49]. In SM, KIT is constitutively activated, resulting in MCs proliferation, differentiation, survival, migration, and cytokine production.

Figure 4

Proposal treatment algorithm for systemic mastocytosis. Proposal treatment algorithm for systemic mastocytosis. SM-AHN, systemic mastocytosis associated a hematological neoplasm; ISM, indolent systemic mastocytosis; SSM, smoldering systemic mastocytosis; ASM, aggressive systemic mastocytosis; MCL, mast cell leukemia; HSCT, hematopoietic stem cell transplant; * Enroll patients in clinical trial, if available.