A possible role has been identified for targeting eosinophils in individuals with nonadvanced systemic mastocytosis (SM) who are not completely controlled by other treatments, according to findings from a retrospective study conducted in France and recently published in The Journal of Allergy and Clinical Immunology.
Patients with mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults. have an abnormal expansion of clonal mast cells, which may generate damage in various body tissues, organs and systems, and is associated with the release of mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. mediators. Cutaneous mastocytosis is recognized as being a skin-limited condition, whereas SM exhibits extracutaneous involvement, including in the bone marrow, liver, spleen and gastrointestinal tract, which affects a considerable percentage of the patient population.
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Despite most cases of mastocytosis sharing the common somatic gain-of-function D816V KIT mutation, SM is recognized as being a heterogeneous disorder with diverse clinical presentations. The various types of mastocytosis are defined based on 2022 World Health Organization criteria and the International Consensus Classification of SM, which comprises the following:
- Bone marrow mastocytosisBone marrow mastocytosis A subtype of indolent SM that occurs when the excess mast cells accumulate in the bone marrow, but not the skin or other organs. (BMM)
- Indolent SMIndolent SM A subtype of nonadvanced SM caused by the abnormal accumulation of mast cells in the bone marrow and other organs. Indolent SM accounts for around 90% of SM cases. (ISM)
- Smoldering SMSmoldering SM A subtype of nonadvanced SM, with a higher mast cell burden than the indolent subtype. Smoldering SM has a higher likelihood of progressing to an advanced form. (SSM)
- SM with an associated hematologic neoplasm (SM-AHN)
- Aggressive SMAggressive SM A subtype of advanced SM marked by a high mast cell burden that leads to organ damage. Aggressive SM accounts for less than 10% of SM cases. (ASM)
- Mast cell leukemiaMast cell leukemia The most severe subtype of SM, caused by the rapid buildup of immature mast cells in the bone marrow and blood. Mast cell leukemia accounts for less than 5% of SM cases and has a poor prognosis. (MCL)
- Mast cell sarcoma
The most common variant is ISM, which is reported in approximately 50% of individuals. Patients with this form of the disease typically have a normal life expectancy and experience no organ failure, although they do report a variety of symptoms, some of which may be severe, such as flushes, hives, pruritus, diarrhea, nausea, vomiting, depression, and memory and cognitive dysfunction. General symptoms are reported as well, including fatigue, asthenia, and brain fog. Anaphylactic episodes may occur spontaneously; alternatively, such attacks may be triggered by insect bites.
Recognizing that bone marrow eosinophilia and, to a lesser extent, blood eosinophilia, is common among individuals with SM but that its implication remains to be determined, the researchers sought to delineate blood and bone marrow eosinophil characteristics of patients with SM.
Bone marrow biopsies were examined with the use of immunohistochemical staining and whole-slide imaging. Eosinophil peroxidase (EPX) staining was used for detection of eosinophil and extracellular granules; KIT staining was utilized to detect mast cells. Immunofluorescence and flow cytometry were used to perform complementary analyses.
The current retrospective study was carried out in the national reference centers for mastocytosis (CEREMAST) network. A total of 61 bone marrow biopsies from 61 patients with SM were included:
- BBM: n=10
- ISM: n=23
- SSM: n=4
- SM-AHN: n=13
- ASM: n=8
- MCL: n=3
There were eight normal biopsies used as controls. Overall, those with BBM, ISM and SSM were included in the nonadvanced SMNonadvanced SM In these subtypes of SM, mast cells accumulate in the body but do not usually cause severe organ damage. Nonadvanced SM includes the subtypes indolent SM and smoldering SM. group, whereas patients with SM-AHN, ASM and MCL comprised the advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm. group.
Results of the study revealed that EPX staining surface was significantly higher among those with nonadvanced SM, compared with both controls and those with advanced SM.
In patients with nonadvanced SM, positive associations were seen between serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. concentrations and percentages of eosinophil counts in bone marrow aspirations, eosinophil counts in bone marrow biopsies, EPX staining and eosinophil degranulation.
Moreover, eosinophil counts in bone marrow biopsies were also significantly associated with mast cell counts and KIT staining surface. Bone marrow mast cells expressed the interleukin-5 receptor and other typical eosinophil cytokine/chemokine receptors. In addition, blood eosinophils exhibit a number of elevated surface markers compared with controls, thus implying an activated state.
“Our data highlight the potential role of eosinophils in [nonadvanced] SM, particularly in ISM,” the authors noted. “[P]rospective clinical trials are warranted to assess the potential benefits of anti-IL-5 or anti-IL-5Rα therapies in reducing both eosinophil-induced [mast cell] activation and directly mitigating [mast cell] activation in [nonadvanced] SM,” they concluded.
