Systemic mastocytosis: current status and challenges in 2024

Abstract

Systemic mastocytosis (SM) is a rare disease and has had significant discoveries in its biology, prognostication, and management in the past 2 decades. The latest update of the World Health Organization classification and the new International Consensus Classification are current standards in the diagnosis and prognostication of SM. In clinical practice, SM can be divided into 2 main categories: nonadvanced SM (nonAdvSM) and advanced SM (AdvSM). The integration of clinical signs and symptoms as well as bone marrow morphologic, immunophenotypic, and molecular results is required to diagnose SM variants. In the modern era, data with KIT inhibitors (ie, avapritinib) suggest prolongation of survival in AdvSM. Although this is encouraging progress, and we now have effective drugs for managing both patients with indolent SM and AdvSM, there are remaining challenges in SM. For example, optimal initial treatment in certain patient subsets, such as SM with an associated hematologic neoplasm (SM-AHN), remains under debate (eg, treatments targeting AHN or SM, monotherapy, or combinations). Prospective studies evaluating drugs with different mechanisms of action are needed for such patients. This review provides an updated overview of SM, including the latest methods for diagnosis, patient classification based on their prognosis, and management according to the most significant clinical trials, covering both patients with nonadvSM and AdvSM.

Graphical abstract

Figure 1.

Classification and clinical features of SM according to revised WHO classification (fifth edition) in 2022 and ICC.^aThese findings are defined as B-findings. ^bThese findings are defined as C-findings. ^#Bone marrow dysfunction manifested by ≥1 cytopenias (absolute neutrophil count of <1 × 10⁹/L, hemoglobin [Hb] of <10 g/dL, platelets of <100 × 10⁹/L but no obvious non-MC hematopoietic malignancy. ^##Liver dysfunction with ascites, and/or portal hypertension. ^###Large osteolytic lesions and/or pathologic fractures. Of note, ICC includes BMM in ISM and uses associated myeloid neoplasm (AMN) instead of AHN in the subset of SM-AHN. Also, by ICC, a core biopsy specimen may be used to diagnose MCL if the aspirate is a “dry tap.”

Figure 2.

Urticaria pigmentosa in a patient with SSM. Informed consent and written permission were obtained from the patient.

Figure 3.

Diagnostic algorithm of SM. ∗Reactive causes are excluded, and criteria for other myeloid neoplasms are not met. ∗∗Lymphadenopathy as a B-finding is defined as >1 cm and 2 cm according to ICC and fifth edition of the WHO classification, respectively. ANC, absolute neutrophil count; PLT, platelet.

Figure 4.

Bone marrow findings in SM. All images captured using a ×20 objective. (A) Hematoxylin and eosin–stained section of a BM core shows an atypical, partially paratrabecular MC aggregate composed of numerous spindle-shaped MCs. There is a reactive lymphoid aggregate present adjacent to the MC aggregate (confirmed by IHC [not shown] and concurrent negative flow cytometry for B and T cells). The MCs uniformly express strong CD117 (B) and MC tryptase (C). The MCs also aberrantly express CD25 (D) but lack CD2 or CD30 expression (not shown). Morphology and flow cytometry also excludes a myeloid neoplasm. Although a flow study was attempted to analyze the MCs, the patient’s involvement was patchy; there were too few MCs on the flow study to interpret CD2 and CD25 expression.

Figure 5.

Flow cytometry findings in SM. Viable singlets are analyzed, and MCs are identified based on their bright surface CD117 expression and high SSC (right angle light scatter that increases in cells with cytoplasmic granules, such as in MCs), left-most plot. Typically, in SM, as in this case, there is a “discrete” MC population based on CD117 vs SSC. The middle plot shows the MCs fall on CD45 vs SSC, falling in an area between in which neutrophils and eosinophils typically fall. The right-most plot shows the aberrant expression of CD2 and CD25 by the MCs (color gated in blue), and the red dots likely correspond to a few residual normal MCs. APC, antigen-presenting cell; FITC, fluorescein isothiocyanate; PE, phycoerythrin; SSC, side scatter.

Figure 6.

Progression timeline from NonAdvSM to AdvSM seems to follow a straight line for SM. However, in SM-AHN, the progression of AHN, SM, or both over time is less predictable because of heterogeneity and limited knowledge of risk factors.

Figure 7.

Treatment approaches of SM.