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Journal of Hematology

Case Report

Volume 13, Number 3, June 2024, pages 128-136

Unraveling the Rare Entity of KIT D816V-Negative Systemic Mastocytosis

Mast cell disorders represent a category of myeloproliferative neoplasms characterized by aberrant clonal mast cell proliferation [1, 2]. These abnormal mast cells infiltrate various tissues and get activated, leading to clinical manifestations mimicking allergic reactions without an identifiable allergic trigger [3, 4]. The International Consensus Classification (ICC) and World Health Organization (WHO) recently updated their classification of mastocytosis. It classified mast cell disorders into cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma (MCS), with further subclassifications depending on the extent of involvement within each category (Table 1) [1, 5-10]. The diagnostic criteria for SM in the WHO fifth edition and in ICC were revised to require a major criterion with one minor or at least three minor criteria (Table 2) [1, 8-11].

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Table 1. The WHO Fifth Edition (WHO 5th) and the ICC Classifications of Mastocytosis

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Table 2. The WHO Fifth Edition (WHO 5th) and the ICC Diagnostic Criteria for SM

SM (SM) is a rare type of mast cell disorder characterized by the infiltration of various tissues, including but not limited to the bone marrow, gastrointestinal organs, and other extracutaneous tissue, by dysregulated mast cells [1, 12]. Although identifying KIT-activating gene mutation, specifically at codon 816, is considered a fundamental part of the diagnosis and is one of the four minor criteria according to the ICC diagnostic criteria for SM, its negativity does not exclude the diagnosis [1, 13]. Few patients do not reveal a KIT mutation; however, these cases are rare [12]. In this case report, we report two cases of KIT-negative SM and a review of the cases reported in the literature. We aimed to enhance our understanding of this exceedingly rare entity’s distinctive features, the diagnosis, and management.

A 49-year-old previously healthy female was referred to our care with a 4-year history of painless and nonpruritic cutaneous eruptions affecting her upper and lower extremities, as well as the abdomen. These eruptions occurred spontaneously, without identified triggers. In the year preceding her hospital visit, the patient experienced unexplained episodes of dizziness accompanied by nausea and vomiting. The diagnostic investigation revealed thrombocytopenia (C-finding) and a high serum tryptase level (157 µg/L). Computed tomography (CT) imaging showed splenomegaly (B-finding) and multiple lytic lesions (C-finding) (Table 3) [1, 9]. A subsequent bone marrow biopsy disclosed 70% cellularity, with 40% mast cells, consistent with SM. Immunostaining was positive for CD117, CD68, and tryptase, while molecular testing from the peripheral blood using polymerase chain reaction (PCR) to amplify exons 8, 9, 11, 13, and 17 of c-KIT was negative. Attempts to get a sample for the bone marrow were unsuccessful as they resulted in a dry tap. There was no evidence of other concomitant hematological malignancy on bone marrow examination. Positron emission tomography (PET)/CT scan illustrated fluorodeoxyglucose (FDG)-avid generalized skeletal sclerosis attributable to the underlying SM. The patient was started on imatinib along with symptomatic treatment such as topical clobetasol, famotidine, and loratadine, which led to improvement in the skin lesions, although she reported muscle aches, which were attributed to medication-related adverse effects. The patient is presently well maintained on a regimen of 300 mg of imatinib daily 2 years from the initial presentation.

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Table 3. The WHO Fifth Edition Summarizing the Clinical Findings of SM, Classified Into B-Findings and C-Findings (Adapted From Valent et al [1, 9])

A 40-year-old male, known to have bronchial asthma, sought medical attention for recurrent anaphylactic episodes marked by syncope, skin manifestations, respiratory distress, and gastrointestinal symptoms. The clinical presentation, initially triggered by physical exertion and later associated with specific dietary factors, prompted comprehensive diagnostic investigations. These episodes started at the age of 30 years and manifested as sudden-onset headaches, palpitations, and flushing, followed by an episode of brief loss of consciousness. The evaluation revealed eosinophilia, prompting bone marrow biopsy, which revealed indolent SM, demonstrating multifocal infiltration by atypical mast cells expressing tryptase, CD117, and CD25. Cytogenetic studies were negative for PDGFR alpha and beta rearrangements, and molecular testing from the bone marrow sample using PCR to amplify exons 8, 9, 11, 13, and 17 of c-KIT was negative, as well as testing of the KIT mutation through the myeloid next-generation sequencing (NGS) panel on the bone marrow samples, returned negative results. There was no evidence of an associated myeloid neoplasm on bone marrow review. Therapy with midostaurin was started, while continuing on supportive therapy which included montelukast, cetirizine, and inhaled intranasal and systemic steroids (prednisolone 5 mg daily), resulting in a significant reduction in symptom frequency. However, subsequent challenges in medication availability led to sequential transitions to dasatinib, which was changed later to imatinib due to poor response, and ultimately avapritinib after developing another anaphylactic reaction 9 months after starting imatinib. The patient is well managed with avapritinib and has a complete clinical response; however, he developed hair and skin depigmentation, attributed to avapritinib treatment (Fig. 1).

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Figure 1. Case 2: skin and hair color pre (left) and post (right) avapritinib treatment. Wild-type KIT signaling is involved in melanogenesis and hair pigmentation, and inhibition can result in hair depigmentation and lightning of the skin through a temporary melanocyte dysfunction. Avapritinib skin and hair changes were reported in 6% to 21% of treated patients.

SM represents a rare and aggressive entity within the spectrum of mast cell disorders, featuring further subclassifications according to the ICC that vary in severity, including indolent SM (incorporating bone marrow mastocytosis), smoldering SM, aggressive SM, SM with an associated hematologic neoplasm (AHN-SM), and mast cell leukemia (MCL) (Table 1) [1, 8-10].

Mastocytosis is often linked to somatic gain-of-function point mutations in the KIT gene, namely at the D816V domain, where aspartic acid is replaced by valine, resulting in unregulated proliferation, amplified growth, and increased survival of mast cells [14, 15]. Various cellular entities, including mast cells, hematopoietic progenitor cells, germ cells, melanocytes, and interstitial cells of Cajal within the gastrointestinal tract, manifest the expression of KIT, a type III receptor belonging to the tyrosine kinase family encoded by a 21-exon containing gene located on chromosome 4q12 [9, 16-19]. In normal circumstances, the KIT gene is downregulated upon the maturation of all hematopoietic progenitor cells, except for mast cells. Mast cell surfaces express KIT genes at high levels. However, the stem cell factor, a ligand for KIT, controls the mast cell activity [9, 15]. Other less common mutations observed in advanced SM encompass, yet are not confined to, TET2, SRSF2, ASXL1, RUNX1, JAK2, N/KRAS, CBL, and EZH2 [13, 20-22]. Although KIT mutations are prevalent, occurring in > 95% of SM cases, their uniform presence is not ubiquitous [12, 23]. The occurrence of KIT-negative cases of SM is notably rare [9, 24]. However, their prevalence has gained increased recognition over the years, as evidenced by the cases reported in the literature (Table 4) [14, 25-28] and those presented in this paper. Research is still being done to understand better the complex interactions between different mutations, their capacity to change mast cells, and their influence on clinical manifestations and treatment of mastocytosis [9]. Individuals with SM manifest symptoms primarily related to the infiltration of different tissues by mast cells and their activation, which leads to the release of vasoactive mediators and cytokines [3]. The clinical manifestations include episodic flushing, diarrhea, hypotension, osteoporosis, and abdominal pain [4, 14]. In the context of KIT-negative SM, there is not enough evidence on the specific features seen in this entity; however, there is evidence expressing its association with advanced SM subtypes, such as MCL and MSC [12, 29]. According to the cases we have reported and reviewed in the literature, the clinical symptoms seem similar to those of KIT-positive SM (Table 3) [1, 9]. Additional features reported in the sparse cases available in the literature include dizziness, nausea, vomiting, headache, fatigue, weight loss, memory problems, insomnia, exertional dyspnea, joint pain, lower gastrointestinal bleeding, and compression fractures [14, 25-28]. By assessing both our reported KIT-negative SM cases and those documented in the literature, we can see that there appears to be a noticeable diversity in clinical manifestations. This spectrum includes a range of symptom types and varying degrees of severity, collectively emphasizing the notable variability in this condition (Table 3) [1, 9].

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Table 4. Clinical and Pathologic Comparison of Our SM Cases and Cases in the Literature

Detecting KIT-activating point mutations is typically done using molecular biology techniques, precisely PCR in conjunction with DNA sequencing [9, 15, 30]. The ability to detect the KIT-D816V mutation relies on the sensitivity of the test used and the concentration of mast cells in the sample [31]. KIT-D816V testing from whole blood has been reported to have high specificity but limited sensitivity [32]. To enhance the sensitivity of this testing, it has been recommended that the test be performed on purified cell groups, including abnormal mast cells, eosinophils, basophils, and monocytes [32]. However, targeting the affected mast cells or other cell groups makes testing challenging, and this is further complicated by the inconsistency of mast cell infiltration in cases of SM. Several attempts have been made to enhance the sensitivity of detecting KIT mutations in SM [30]. Kristensen et al developed a quantitative and sensitive allele-specific real-time quantitative polymerase chain reaction (qPCR) assay to detect the KIT-D816V mutation [30]. This test detected the mutation in 19 out of 20 SM patients at low levels, as low as 0.03% in bone marrow mononuclear cells [30]. In cases of a negative KIT testing result, applying refined methodologies becomes essential for assessing the results’ reliability, particularly when the mutation detection limit exceeds the proportion of mast cells within the sample, often due to the island-like aggregation of mast cells in the bone marrow [30]. Nevertheless, the genuinely negative KIT mutation is believed to occur in some patients with SM. Further refinement and advancement of methodologies and investigations are needed to improve KIT mutation detection and accurately diagnose KIT-negative SM. NGS can enhance the ability to detect KIT and non-KIT mutations and quantify the variant allele frequency (VAF) of the KIT-D816V mutation [33, 34]. A limitation of our study is the unavailability of the most advanced tools for detecting KIT mutations, which may have led to false-negative results in the cases we reported.

The therapeutic approach to SM depends on the severity of symptoms. Therapy can range from vigilant monitoring to cytoreductive therapy and, in rare and more aggressive cases, stem cell transplantation [9, 34]. Treatment modalities include symptom alleviation, mast cell reduction strategies for disease modification, and the implementation of supportive measures [9].

Symptomatic control involves the regulation of vasoactive mediators and cytokines, achieved through administration of H1 and H2 antihistamines, anti-leukotrienes, and nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin) [9, 34, 35]. Omalizumab, a recombinant humanized monoclonal antibody, improves mastocytosis symptoms by inhibiting immunoglobulin E (IgE) binding to the high-affinity IgE receptor (RI) on mast cells’ surface. Its efficacy is particularly seen in patients experiencing recurrent anaphylaxis [9, 34, 36]. Despite its symptomatic benefits, the Food and Drug Administration (FDA) has not yet approved omalizumab for mastocytosis [9, 36]. Disodium cromoglycate is an organic sodium salt used to treat asthma. It has improved tryptase levels and symptoms in KIT-D816V-negative SM cases [27]. It functions as a mast cell stabilizer and has an anti-inflammatory effect. In the report by Conde-Fernandes et al, the patient turned out to have a different type of KIT mutation, known as the KIT-V560G mutation [27].

Advanced cases require additional interventions, including cytoreductive agents, for example, hydroxyurea, which causes non-targeted myelosuppression, purine analogs such as cladribine, and interferon-α [4, 9, 37-39]. Cladribine has demonstrated efficacy across all the subtypes of SM, with the additional advantage being time-constrained [9, 38]. Interferon-α is less frequently used but may be valuable in areas with modest resources [9, 39]. However, with the rapid evolution in the medical field, advancements in targeted therapies have emerged, which has increased their appeal. The high prevalence of KIT mutations in SM makes it an attractive therapeutic target [40, 41]. Examples of kinase inhibitors that selectively target KIT mutations include avapritinib, approved as first-line therapy for indolent and advanced SM [42-45]. Regarding cases of true KIT-negative SM, it is theorized that therapies that selectively target KIT mutations are less effective when compared to their impact in cases of KIT-positive SM. Therefore, pursuing treatments with alternative mechanisms of action beyond KIT mutation targeting is considered a viable therapeutic strategy when managing such cases. That being said, there is evidence demonstrating the efficacy of avapritinib in cases of KIT-negative SM [25]. This observation is highlighted in some of the cases reported, including one of ours (Table 3) [1, 9]. Gotlib et al explored the efficacy of midostaurin, a potent multi-kinase inhibitor, in cases of advanced SM and reported a response rate of up to 60%, irrespective of KIT-mutation status [46, 47]. Alternatively, tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib are used in cases of KIT-negative SM. Interestingly, KIT-positive SM patients respond poorly to various TKIs, especially to imatinib, as KIT-D816V mutations result in primary resistance [48-51]. Nonetheless, there has been significant heterogeneity in the responsiveness to different TKIs across the reported cases of KIT-negative SM (Table 3) [1, 9].

Multiple medications are being investigated for efficacy in SM, including bezuclastinib, an orally administered potent and selective type I TKI targeting multiple loci, including D816V [52-54]. BLU-263 is an orally administered selective inhibitor targeting KIT D816V [55, 56]. Masitinib is a TKI exhibiting activity against wild-type KIT, Lyn, and Fyn kinases [57].

Supportive interventions are vital to managing SM. These measures include avoiding triggers such as aspirin, contrast dyes, anesthesia, narcotics, and alcohol, as well as preventing and managing osteopenia/osteoporosis [9, 34].

The prognosis of SM depends on different factors, including age, cytopenias, the WHO classification-defined subtype of SM, biochemical markers, and mutational profile [58-60]. Multiple prognostic scoring systems are used for advanced and non-advanced SM, e.g., REMA, IPSM, GPS, MARS, and MAPS scoring systems. These scoring systems rely on parameters such as age, blood counts, serum tryptase, β2-microglobulin, alkaline phosphatase, and the mutational profile [20, 21, 34, 61, 62]. The presence of non-KIT mutations, such as SRSF2, ASXL1, RUNX1, and EZH2, has been associated with advanced SM subtypes and inferior prognosis [12, 20-22, 34]. Although a KIT-D816V VAF of > 10% has been linked with a higher tumor burden [63, 64], the prognosis of patients with negative KIT-D816V mutations remains vague. In cases of KIT-D816V-negative SM, these prognostic scores are controversial.

A report by Naumann et al concluded that the conventional scoring systems used in SM cannot be applied in cases of KIT-negative SM and have linked the negativity of KIT in SM with an inferior response to treatment and overall survival [12]. However, in AHN-SM, patients with KIT-D816V-negative mutation had a lower burden of mast cells with the domination of the AHN, which resulted in a better overall survival [12]. In this review, we have reported a case of KIT-D816V-negative SM with an excellent response to avapritinib, along with the reported case by Azad et al (Table 3) [1, 9, 25], which can serve as an initiation point for further comprehensive cohort studies to assess the effect of avapritinib on KIT-D816V-negative SM. The prognostic implications of the KIT D816V mutation require additional investigations to thoroughly establish its influence on overall survival, disease-free survival, and quality of life [14, 60].

SM is a rare disease, and the KIT-D816V-negative SM subset accounts for less than 5% of all cases. This exceedingly rare entity’s specific clinical manifestations, treatment, and prognosis are poorly understood. Further and more comprehensive research is needed to expand our understanding of KIT-D816V-negative SM and determine the most appropriate management and prognosis.

Acknowledgments

None to declare.

Financial Disclosure

This report is not funded by a specific grant.

Conflict of Interest

Mansour Alfayez: Honoraria: Johnson & Johnson, Pfizer, Astellas, Novartis, Amgen, AstraZeneca, AbbVie; Advisory board: Johnson & Johnson, Biologix, Eli Lilly; Research support: Abbvie, AstraZeneca. Other authors declare no conflict of interest with this manuscript.

Informed Consent

Informed consents were obtained.

Author Contributions

RA, CAA, SA, AH, and SKA compiled and summarized the data. RA, SOA and MA treated the patient and wrote the article. All authors contributed, reviewed, and edited the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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