Cases Of Systemic Mastocytosis Research Articles

Osteoporosis in Systemic Mastocytosis: A Scoping Review

Background: Mastocytosis (MS) is a rare disease that can involve various organs, including the bone. Given the incidence of the disease in the global population, MS poses a challenge for physicians, and early therapeutic intervention in the initial stages could significantly impact the quality of life of affected patients. Objective: The aim of this scoping review was to provide an overview of secondary osteoporosis in systemic mastocytosis (SM), focusing on the heterogeneity of its manifestations, the benefits of early diagnosis, and appropriate pharmacological treatment. Design: A technical expert panel (TEP) consisting of 8 physicians with expertise in metabolic bone diseases conducted the review following the PRISMA-ScR model. A strength of this study is that it provides various therapeutic approaches for patients with bone involvement in SM, although the limited available literature on the topic constituted a limitation. The TEP sought evidence regarding the following diagnostic and therapeutic modalities in the management of SM: “bisphosphonate therapy”, “zoledronic acid therapy”, “denosumab therapy”, “IFN-alpha therapy”, and “IFN-alpha therapy in combination with pamidronate”. Results: Clinical data showed a correlation between densitometric outcomes, serum tryptase levels, and mast cell infiltration in the bone marrow, between increased bone mineral density and the presence of osteosclerosis in cases of advanced SM, between the severity of osteoporosis and hypertryptasemia, and also provided results on the long-term effects of bisphosphonate therapy, the therapeutic efficacy of zoledronic acid administration, the positive effect of denosumab on the reduction of serum tryptase levels (even if is proved in a limited numbers of cases) and the prevention of new fractures, and the effect of IFN-alpha in more severe cases of SM, either alone or in combination with pamidronate. Conclusions: Studies have demonstrated the effectiveness of various treatments depending on the form of mastocytosis, whether indolent systemic or advanced systemic, in the prognosis of the disease. However, this role should be further investigated in additional clinical studies, considering the limited data on the use of these interventions.

Epidemiology of mast cell leukemia: A must!

e18537 Background: Mast Cell Leukemia (MCL) is one of the rarest encountered malignancies. It is an aggressive oncologic subtype of systemic mastocytosis (SM) and accounts for <1% of total cases. To make the diagnosis of MCL, in addition to the diagnostic criteria for SM (enlisted in the table), ≥ 20% atypical mast cells should be present in the marrow or ≥ 10% in the peripheral blood. However, an aleukemic form also exists. It can either occur as a de novo mutation or follow mastocytosis. The aim of this epidemiologic study is to aid better understanding of this lesser known aggressive malignancy. Methods: The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Systemic Mastocytosis and Mast Cell Leukemia cases diagnosed after 20 years of age, using the ICD Code 9741/3 (SM) and 9742/3 Mast Cell Leukemia (MCL). The analysis was stratified for MCL based on age, sex, race, and treatment modality used. Results: A total of 795 cases of SM were identified, which were diagnosed between 2000 and 2020. Of which, only 35 cases were attributed to MCL over the last two decades. Of these 35 cases, 60% patients were males, and 40% were females. ~82.85% were Caucasians, ~11.42% were African-Americans, ~2.85% belonged to Asians and Pacific Islanders, and ~2.85% belonged to the Hispanic population. No reported cases were found amongst Alaskan Natives. Further analysis based on survival, gender and races was not done, due to small sample size. Conclusions: MCL accounts for only about 4% of total SM cases. Only 35 cases were identified in the past twenty years, making it one of the rarest encountered malignancies. From the reported data, it was slightly inclined to have male predilection, and Caucasians were the most commonly impacted individuals. Given its extremely low incidence, more research and analysis is warranted to understand this lesser known malignancy. [Table: see text]

Two cases of systemic mastocytosis with RUNX1-RUNX1T1 positive acute myeloid leukemia treated with sequential avapritinib after allogeneic hematopoietic stem cell transplantation and literature review

Systemic mastocytosis (SM) with RUNX1-RUNX1T1 positive acute myeloid leukemia (AML) is a rare myeloid tumor with no standard treatment. Two cases of SM patients with RUNX1-RUNX1T1 positive AML treated with sequential avapritinib after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were reported in Henan Cancer Hospital. Mast cell in bone marrow disappeared, C-KIT mutation and RUNX1-RUNX1T1 fusion gene remained negative. Allo-HSCT sequential avapritinib is an effective treatment for SM patients with RUNX1-RUNX1T1 positive AML.

Histological characterization of liver involvement in systemic mastocytosis.

Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Multicolor flow cytometric immunophenotyping is highly sensitive and specific in identifying aberrant mast cells in the diagnostic workup of systemic mastocytosis.

Flow cytometric immunophenotyping (FCI) is a fast and sensitive method for characterizing hematolymphoid neoplasms. It is not widely used in the workup of systemic mastocytosis (SM), in part because of the technical challenges and in part because the utility of FCI in assessing mast cells is not well understood. The objectives of this study were to assess the diagnostic utility of FCI in establishing a diagnosis of SM and distinguishing SM from nonneoplastic mast cells and to examine the immunophenotypic findings among SM subtypes. We performed FCI on bone marrow samples suspicious for SM using a panel consisting of CD2, CD25, CD30, CD45, CD117, and HLA-DR. The cohort included 88 SM cases: 67 without an associated hematologic neoplasm (AHN) (PureSM) and 21 with an AHN (SM-AHN). We also assessed 40 normal/reactive controls. Overall, FCI was adequate for interpretation in 87 of 88 (99%) cases and detected at least 1 immunophenotypic aberrancy in 100% of SM cases. CD2, CD25, and CD30 were positive in 78%, 98%, and 90% of SM cases vs 0%, 13%, and 13% of cases with normal/reactive mast cells (P < .0001 for all). Two or 3 abnormalities were observed in 92% of SM cases but not in normal/reactive mast cells. Among SM cases, SM-AHN showed statistically significant less CD2 (38% vs 91%, P < .0001) and less co-expression of all 3 aberrant markers (CD2, CD25, and CD30 positive in 38% vs 86% of cases; P < .0001) than PureSM. Immunohistochemical analysis showed consistently weaker or focal expression of CD2, CD25, and CD30 than FCI, with CD2 and CD30 being falsely negative in 40% and 50% cases, respectively. A KIT D816V mutation was detected in 67% of PureSM cases and 76% of SM-AHN cases. Flow cytometric immunophenotyping is a quick, sensitive, high-yield tool for evaluating the immunophenotype of mast cells. An abnormal FCI finding should prompt careful histologic evaluation and sensitive KIT D816V mutation testing to address the possibility of SM. CD2, CD25, and CD30 are important markers for the detection of immunophenotypic aberrancy of mast cells, and their frequencies of aberrancy differ across SM subtypes.

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO &amp;gt; 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and &amp;lt; 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Recent advances in diagnosis and therapy in systemic mastocytosis.

Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

Patterns of Disease Progression in Patients with Systemic Mastocytosis: A US Population-Level Analysis Using Health Claims-Based Dataset

Background Systemic mastocytosis (SM) is a rare clonal mast cell neoplasm driven by the KIT D816V mutation in ~95% of patients (pts). SM includes AdvSM (aggressive SM, SM with associated hematological neoplasm, and mast cell leukemia) and non-advanced SM (indolent & smoldering SM), which accounts for ~95% of cases. The uncontrolled proliferation and activation of mast cells can cause severe & unpredictable symptoms resulting in debilitation, reduced QOL, and organ infiltration and damage with reduced survival in AdvSM. While WHO criteria differentiate between subtypes of mastocytosis, there remains a lack of understanding of patterns of disease progression between SM subtypes. In this analysis we developed a novel claims-based algorithm to identify SM cases and assess disease progression. Methods Using a large, nationally representative claims database, we identified a cohort of SM pts with observed claims activity in each of the year 2019-2022. We developed a novel claims-based algorithm based on WHO diagnostic criteria (2016), including codes for laboratory tests, procedures, and treatments typically used for management of SM. Pts were included if they fulfilled 1 of the following criteria: had ≥2 diagnoses with an SM-specific ICD-10 code (D47.02, C96.21, C94.3X) at least 30 days apart in any setting of care; bone marrow biopsy followed by 1 SM diagnosis (dx) claim code in any setting of care; or 1 SM dx code in any setting of care & at least 1 prescription claim for an SM-specific treatment (avapritinib, midostaurin, imatinib, cladribine, interferons, brentuximab, omalizumab, montelukast, or cromolyn sodium). Pts were then categorized as either AdvSM, higher symptom ISM (ISM-higher), or lower symptom ISM (ISM-lower) based on additional disease-specific codes (Table 1) accumulated over the pt's total observable claims history, from 2015 to the date of evaluation. For pts who met these criteria, SM subtyping was evaluated as of Dec 31, 2019, Dec 31, 2020, and Dec 31, 2021. Treatment rates of select SM-directed therapies were also evaluated over the 12- month period from Jan-Dec, 2021. Results Of 10,939 pts with SM, 80% (8,707 pts) with claims in each of the years 2019, 2020, 2021 and 2022 were included. The first analysis looked at pts’ disease category as of Dec 2021 and assessed utilization of several SM-directed Rx therapies. This included 1,587 AdvSM, 2,705 ISM-higher, and 4,415 ISM-lower pts. Among pts across all cohorts, the most frequently observed therapies were anti-mediator therapies (AdvSM 20%, ISM-higher 37%, ISM-lower 20%) and cromolyn sodium (AdvSM 10%, ISM-higher 19%, ISM-lower 12%). When evaluating disease category evolution, 11.3% and 18.8% of pts with ISM-low migrated to ISM-higher or AdvSM over a 12-month (Dec 2020 - Dec 2021), or 24-month (Dec 2019 - Dec 2021) interval respectively. Across all ISM types, 2.2% of pts progressed to AdvSM in a 12-month interval, and 3.9% progressed to AdvSM over a 24-month interval. Among those pts who emerged with AdvSM in a 12-month interval ending Dec 2021 (N=392), 33% progressed from ISM-Lower or ISM-higher while 67% appeared as de novo diagnoses. Conclusions This study used a large claims dataset to identify pts with SM, classified them with a novel algorithm, and describe patterns of disease progression over a 12-month or 24-month interval. Of note, while this algorithm has been developed with expert clinical input, inherent limitations of claims and a single ICD-10 code for SM leave some ambiguity around the true clinical dx of these pts. Despite this, these analyses reflect the accumulation of severe symptoms over time by a meaningful subset of pts. Approximately 35% of pts with an SM dx did not have a SM dx 2 years prior, possibly due in part to the recency of the SM ICD-10 codes and also raising concerns regarding timely dx. Further, not all ISM pts demonstrated truly indolent disease behavior, illustrated by the 30% of ISM pts categorized as ISM-high requiring greater use of symptom-directed and disease-specific therapies. Finally, the proportion of AdvSM pts on FDA-approved TKI-directed therapies remain low, highlighting large unmet treatment need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes of Adults with Systemic Mastocytosis: A 15-Year Multidisciplinary Experience.

Simple SummaryThe term mastocytosis denotes a heterogeneous group of rare disorders characterized by abnormal accumulation and activation of mast cells in various organs. Based on the WHO classification, mastocytosis can essentially be split into indolent and advanced systemic disease. Indolent mastocytosis is the most prevalent variant in adults. In our retrospective study, we aimed to analyze the clinical outcomes of patients with mastocytosis attending our center over the last 15 years. We found that most patients in our cohort suffered from the indolent variant of mastocytosis. Furthermore, we determined the overall prevalence of mastocytosis in our region to be one case per 10,000 adults. In addition, overall survival was significantly better in indolent mastocytosis patients compared to patients with advanced disease. Therefore, awareness of differences in the prognoses of patients with indolent and advanced mastocytosis is important.Systemic mastocytosis (SM) is a rare, clonal, clinically heterogeneous disorder of the mast cells (MCs), and mainly affects adults. The present study aims to describe the clinical and laboratory features as well as the outcomes of SM. A 15-year retrospective study was conducted on 195 consecutive SM patients (aged ≥ 18 years) diagnosed in 2006–2020 at the Multidisciplinary Mastocytosis Center at Karolinska University Hospital. Patients with indolent SM (ISM) represented the most common SM variant (88.2%). Furthermore, the frequencies of aggressive SM and SM with associated non-mast-cell hematological neoplasm were 4.1% and 7.7%, respectively. The prevalence of SM in the adult population of the Stockholm region was estimated to be 10.6/100,000 inhabitants, and the mean incidence of SM cases in the Stockholm region was 0.77/100,000 people per year. In this series, tryptase levels were below 20 ng/mL in 51 patients (26%). Osteoporosis was present in 21.9% of all cases. Interestingly, there was no progression from ISM to advanced SM variants in our study. Furthermore, overall survival was significantly better in ISM patients compared to advanced SM patients (p < 0.0001). Our data suggest that the early recognition and correct diagnosis of SM has prognostic significance.

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis.

Simple SummarySystemic mastocytosis (SM) is a clonal haematopoietic stem cell disease typically characterized by the expansion and accumulation of neoplastic mast cells carrying the activating KIT D816V as a driver mutation. Multilineage involvement of haematopoiesis by this KIT mutation, particularly in a multi-mutated context, also involving other genes (e.g., SRSF2, ASXL1, DNMT3A, RUNX1, EZH2, CBL and NRAS) found to be frequently mutated in other myeloid neoplasms, have recently emerged as a genetic background associated with malignant transformation of SM. Therefore, assessment of multilineage involvement of haematopoiesis by KIT D816V and additional mutations in genes known to be associated with the prognosis of SM have become of great help to identify good vs. poor-prognosis SM patients who could benefit from a closer follow-up and, eventually, also early cytoreductive treatment.Systemic mastocytosis (SM) is a rare clonal haematopoietic stem cell disease in which activating KIT mutations (most commonly KIT D816V) are present in virtually every (>90%) adult patient at similar frequencies among non-advanced and advanced forms of SM. The KIT D816V mutation is considered the most common pathogenic driver of SM. Acquisition of this mutation early during haematopoiesis may cause multilineage involvement of haematopoiesis by KIT D816V, which has been associated with higher tumour burden and additional mutations in other genes, leading to an increased rate of transformation to advanced SM. Thus, among other mutations, alterations in around 30 genes that are also frequently mutated in other myeloid neoplasms have been reported in SM cases. From these genes, 12 (i.e., ASXL1, CBL, DNMT3A, EZH2, JAK2, KRAS, NRAS, SF3B1, RUNX1, SF3B1, SRSF2, TET2) have been recurrently reported to be mutated in SM. Because of all the above, assessment of multilineage involvement of haematopoiesis by the KIT D816V mutation, in the setting of multi-mutated haematopoiesis as revealed by a limited panel of genes (i.e., ASXL1, CBL, DNMT3A, EZH2, NRAS, RUNX1 and SRSF2) and associated with a poorer patient outcome, has become of great help to identify SM patients at higher risk of disease progression and/or poor survival who could benefit from closer follow-up and eventually also early cytoreductive treatment.

A Multidisciplinary Diagnostic Approach Reveals a Higher Prevalence of Indolent Systemic Mastocytosis: 15-Years' Experience of the GISM Network.

Simple SummaryThe approach of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona, based on a regional network of clinical specialists and expert pathologists, with the availability of sensitive molecular and flow-cytometry diagnostic techniques, allowed the discovery of a higher-than-expected number of patients with systemic mastocytosis (SM), demonstrating a prevalence of 17.2/100,000 adult inhabitants. During a 15-year period of activity, we documented a remarkable increase in diagnosis of indolent SM, which constitute over 90% of our SM series, mainly represented by the bone marrow mastocytosis subvariant (54.8%). A timely diagnosis of SM has a great practical importance, since allows discovering and treating underdiagnosed osteoporosis, especially in males, a condition which is frequently complicated with fragility fractures, also in young patients, with disabling consequences. Moreover, diagnosis of mastocytosis in patients with Hymenoptera venom allergy allows continuing lifelong venom immunotherapy in order to prevent further severe, sometimes fatal, allergic reactions.Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence and incidence of CMD. We examined the data of 502 adult patients diagnosed with CMD and residing in the Veneto Region, consecutively referred to GISM between 2006 and 2020. SM was diagnosed in 431 cases, while 71 patients had cutaneous mastocytosis or other CMD. Indolent SM represented the most frequent SM variant (91.0%), mainly with the characteristics of bone marrow mastocytosis (54.8%). The prevalence of SM in the adult population of the Veneto region and of the Verona province was 10.2 and 17.2/100,000 inhabitants, respectively. The mean incidence of new SM cases in Verona was 1.09/100,000 inhabitants/year. Hymenoptera venom allergy was the main reason (50%) leading to the CMD diagnosis. Osteoporosis, often complicated by fragility fractures, was present in 35% of cases, even in young patients, especially males. Our data show a higher prevalence and incidence of SM than previously reported, confirming that reference centers with multidisciplinary approach are essential for the recognition and early diagnosis of CMD.

The Expressions of CD30 and CD123 of Mastocytosis in Taiwan.

Mastocytosis is a rare disease with a low incidence in Asia-Pacific populations. CD30 and CD123 may have potential prognostic and therapeutic value, but the results are inconsistent. Because racial disparities may exist, we aim to evaluate the expressions of CD30 and CD123 in a series of mastocytosis cases in Taiwan. Twelve patients with systemic and 7 with cutaneous forms of mastocytosis were studied. The expressions of CD30 and CD123 were correlated with the clinical features of the patients. Eighty-three percent (10/12) of patients with systemic mastocytosis (SM) had an associated hematological neoplasm. Four of the SM patients had both "B" and "C" findings, and they had a median survival time of 0.9 months. CD30 expression was positive in 50% (6/12) of SM cases and 100% (6/6) of cutaneous mastocytosis cases. CD123 was expressed focally or weakly in only 2 SM-associated hematological neoplasm cases. The distribution of mastocytosis subtypes and the expression of CD30 and CD123 in Taiwan differed from those reported in North America and Europe. However, mastocytosis, especially indolent forms, is easily overlooked as its heterogeneous and nonspecific clinical manifestations. A high index of suspicion and improved diagnostic methods can be helpful.

ERG Immunoreactivity in Blastic Hematolymphoid Neoplasms: Diagnostic Pitfall in the Workup of Undifferentiated Malignant Neoplasms.

Undifferentiated malignant neoplasms pose diagnostic challenges, and reliable immunohistochemical markers with well-characterized staining profiles are desirable when characterizing them. Our initial observation of erythroblast transformation specific regulated gene-1 (ERG) reactivity in myeloid sarcomas led us to broadly explore the utility of ERG as a marker of immature hematolymphoid neoplasms presenting in extramedullary sites. We stained 207 immature and mature hematolymphoid lesions as well as 39 benign hematolymphoid tissues and found weak-to-moderate ERG immunopositivity in 15 of 16 (94%) acute myeloid leukemias/myeloid sarcomas, including 4 of 5 (80%) CD34-negative/CD117-negative acute myeloid leukemias/myeloid sarcomas. ERG positivity was also seen in all 9 cases of B-lymphoblastic and T-lymphoblastic leukemia/lymphoma, all 3 cases of hematogone hyperplasia, and all 4 cases of systemic mastocytosis. ERG was negative in 148 mature B-cell and T-cell lymphomas, including 2 high-grade B-cell lymphomas and 2 blastoid variant mantle cell lymphomas; 23 histiocytic/dendritic cell neoplasms; 2 indolent T-lymphoblastic proliferations; and 2 blastic plasmacytoid dendritic cell neoplasms. We conclude that ERG immunoreactivity may pose a significant diagnostic pitfall in the workup of undifferentiated malignant neoplasms, particularly those presenting in extramedullary sites.

An Intriguing Coexistence of Cutaneous and Systemic Mastocytosis with Atypical Chronic Myeloid Leukemia

Systemic mastocytosis (SM) characterized by focal or diffuse infiltrates of neoplastic mast cells can range from indolent cutaneous disease to aggressive systemic disease. Skin involvement is usual in indolent systemic mastocytosis, less frequent in aggressive SM, and rare in mast cell leukemia. Here, we present a rare coexistence of cutaneous mastocytosis and SM with an associated hematologic neoplasm SM-associated hematologic neoplasm [AHN] (atypical chronic myeloid leukemia [CML]-BCR/ABL negative), the first case being reported in the literature so far to the best of our knowledge. An elderly male with leukocytosis, myeloid hyperplasia, and mast cell infiltrates in the marrow was diagnosed with atypical CML and cutaneous mastocytosis. Approximately 40% of cases of SM are associated with a hematologic neoplasm (SM-AHN) encompassing all defined myeloid neoplasms, such as myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, CML, chronic myelomonocytic leukemia, or plasma cell myeloma. The prognosis of SM-AHN is dependent on the associated hematologic neoplasm (AHN).

Treatment of Mastocytosis: A Literature Review

The term “mastocytosis” refers to a group of rare heterogeneous disorders resulting from proliferation and accumulation of neoplastic mast cells in various organs. The World Health Organization (WHO) classifies these diseases into three types: cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma (MCS). Depending on the degree of aggressiveness SM can be indolent, smoldering, aggressive (ASM), or associated with another proliferative hematological disease of non-mast cell line (SM-AHD). SM also includes mast cell leukemia (MCL). Numerous studies confirm the prognostic value of the WHO classification. All mastocytosis patients require treatment aimed at reducing the symptoms of mast cell activation. In case of prognostically unfavorable types of mastocytosis, such as ASM, SM-AHD, MCL, and MCS, more intensive treatment methods should come into consideration, which include allogeneic hematopoietic stem cell transplantation, cytoreductive therapy with tyrosine kinase inhibitors (TKI), interferon-α, and cladribine. In the pathogenesis of mastocytosis, mutations in different KIT gene exons have a dominating role. Most common is KITD816V activating mutation (80-90 % of SM cases). Some of TKIs (imatinib mesylate and midostaurin) had been successfully used in clinical trials and were approved for treating prognostically unfavorable mastocytosis. However, in some patients exclusive TKI treatment does not result in long-lasting remission due to therapy resistance induced by KIT activating mutations as well as other additional somatic mutations and molecular changes. For the purpose of comparative analysis, the review provides the results of major clinical trials dealing with various methods of mastocytosis treatment.

Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap.

Systemic mastocytosis is a rare and heterogeneous disease characterized by mast cell proliferation and activation. KIT is a transmembrane tyrosine kinase which plays a key role in mast cell growth, differentiation and survival. After interaction with its ligand, the stem cell factor, KIT dimerizes activating downstream pathways involving multiple tyrosine kinases (PI3K, JAK/STAT, RAS/ERK). Activating mutations in KIT are detected in most cases of systemic mastocytosis, being the most common KIT D816V. Therefore, since the emergence of tyrosine kinase inhibitors, KIT inhibition has been an attractive approach when facing mastocytosis treatment. Initial reports showed that only the rare KIT D816V negative cases were responsive to tyrosine kinase inhibitors. However, the development of new tyrosine kinase inhibitors such as midostaurin or avapritinib with activity against mast cells carrying the D816V KIT mutation, has changed the landscape of this disease.

Detection of the KITD816V mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis.

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KITD816V. Prognostically-significant pathogenic KIT mutations also occur in 30-40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KITD816V-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KITD816V, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KITD816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.

Myelodysplasia as assessed by multiparameter flow cytometry refines prognostic stratification provided by genotypic risk in systemic mastocytosis.

Systemic mastocytosis (SM) is characterized by extreme heterogeneity of manifestations and prognosis. Several disease-related biomarkers, including clinical, hematological and molecular variables, have been correlated with prognosis. Although relevant, the mutation profile closely reflects the WHO classification that has per se prognostic value. High-risk mutations (HRM) are largely confined to advanced forms, and thus fail in providing information regarding progression and outcome in the not-advanced variants. In this work, we studied hematopoietic cells by multi-parameter flow cytometry (MFC) in order to highlight dysplastic traits that might provide insights into outcome. A score previously validated for myelodysplastic syndromes, with high reproducibility in standard diagnostics, was used. The application of an MFC score to a cohort of 71 SM cases, concurrently genotyped for configuring a HRM category, resulted in the identification of two separate patients' categories (MFC+ and MFC-) characterized by significantly different clinical and laboratory features at presentation. The extent of dysplasia by MFC tended to parallel WHO-category and genotype-related stratification. MFC+ patients had shorter survival compared to MFC- ones, for whom the incidence of progression and/or death was virtually null. Of note, MFC score remained prognostically informative in unadvanced subsets. Furthermore, the integration of MFC and HRM was an independent predictor for outcome, also overcoming WHO-categories in multivariate analysis for EFS. Our results support the use of MFC analysis in the evaluation of patients with SM, alone and in combination with HRM, for refinement of prognosis assessment.

Cytogenetic Abnormalities in Systemic Mastocytosis: Who Subcategory-Specific Incidence and Prognostic Impact Among 348 Informative Cases

Background:The World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smouldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) (Blood. 2016;127:2391). Recent studies have highlighted the prognostic importance of mutations in SM, including ASXL1, RUNX1 and SRSF2 (AJH 2016;91:888;Leukemia 2016;30:2342). In the current study, we reviewed the cytogenetic findings in 348 cases of SM, in order to clarify incidence and prognostic impact of cytogenetic abnormalities, stratified by WHO morphologic subcategories.Methods:Study patients were selected, based on availability of cytogenetic information. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with WHO criteria (Blood. 2016;127:2391). Next-generation sequencing was performed in a subset of the study population. Abnormal karyotype was further distinguished into favorable and unfavorable class based on previously published criteria for myelodysplastic syndromes (MDS) (Blood 2012;120:2454) and myeloproliferative neoplasms (MPN) (Leukemia 208;32:1189). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic, which coincided with collection of bone marrow for cytogenetic studies. Conventional statistics was used for calculation of overall survival and determination of risk factors. JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations.Results:348 SM patients were included in the current study (median age 59 years; range 18-88 years; 53% males); 142 (41%) constituted ISM and 206 (59%) advanced SM; the latter included 155 (45%) SM-AHN, 49 (14%) ASM and 2 MCL cases. The SM-AHN cases included 39 (11%) SM-MPN, 36 (10%) SM-CMML, 22 (6%) SM-MDS, 22 (6%) SM-myeloid unclassified, 14 (4%) SM-MDS/MPN, 12 (3%) SM-lymphoid malignancy and 10 (3%) SM-acute leukemia. Adverse mutations, including ASXL1 (19% mutated), RUNX1 (3% mutated) and NRAS (3% mutated) were detected in 30 (23%) of 129 cases screened. After a median follow-up of 21 months, 139 (40%) deaths and 6 (5%) leukemic transformations were documented.Karyotype was abnormal in 53 (15%) cases and included unfavorable (n=29; 8%) and favorable (n=24; 7%) abnormalities. Abnormal karyotype incidences were 6% for ISM and 22% for advanced SM (p<0.001). Among advanced SM cases, abnormal karyotype incidences were 26% for SM-AHN and 8% for ASM (p<0.001); one of 2 MCL cases displayed abnormal karyotype. Among SM-AHN cases, abnormal karyotype incidences were 0% for SM-AHN-lymphoid, 28% for SM-AHN-myeloid (p<0.001); the latter included 19% for SM-CMML, 21% for SM-MDS/MPN, 23% for SM-MPN, 36% for SM-MDS and 41% of SM-myeloid-unclassified (p<0.001). Clinical correlative studies disclosed significant associations between abnormal karyotype and male sex (p=0.002), age >60 years (p=0.04), thrombocytopenia (p<0.001; 27% vs 10%) and anemia (p<0.001; 25% vs 6%), but not with the presence of adverse mutations (p=0.19).In univariate analysis, abnormal karyotype was associated with inferior survival (HR 3.0, 95% CI 2.0-4.3) and significance was sustained when analysis was adjusted for two-tiered (advanced vs indolent SM; p<0.01) or multi-tiered (ISM vs ASM vs SM-AHN; p<0.01) WHO subcategories. WHO category-specific analysis clarified prognostic relevance of abnormal karyotype in ASM (HR 4.4, 95% CI 1.0-14.4; p=0.05; figure 1a) and SM-AHN-myeloid (HR 1.9, 95% CI 1.2-2.9; p=0.005; figure 1b); however, the near-significance in ASM was fully accounted for by thrombocytopenia (p value corrected to 0.35) and for SM-AHN-myeloid by thrombocytopenia and anemia (p value corrected to 0.06); further stratification of abnormal karyotype into favorable vs unfavorable categories did not affect the results in ASM but revealed an independent prognostic effect for unfavorable karyotype in SM=AHN-myeloid (p=0.009).Conclusions:Abnormal karyotype in SM clusters with SM-AHN-myeloid. We found no correlation between abnormal karyotype and adverse mutations. Anemia and thrombocytopenia were significantly associated with abnormal karyotype and accounted for the apparent prognostic relevance of the latter in ASM. Unfavorable karyotype carries independent prognostic effect in SM-AHN-myeloid. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical and Molecular Models of Prognostication in Mastocytosis: Analysis Based on 580 Consecutive Cases

Background:The 2016 World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) (Blood. 2016;127:2391). In the current study, we capitalized on the large number of accumulated cases of SM seen at the Mayo Clinic, between 1968 and 2015 (n=580), in order to devise two separate but complementary prognostic models that are based on either clinically-derived variables, or a combination of both clinical and molecular information.Methods:Study patients (n=580) were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with the 2016 WHO criteria (Blood. 2016;127:2391). Next-generation sequencing (NGS) was performed in a subset of the study population (n=150). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic. Conventional statistics was used for calculation and of overall survival and determination of inter-independent risk factors. Receiver operating characteristic (ROC) curves were used to determine the prognostically most discriminative platelet threshold. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations.Results:580 patients with SM (median age 55 years; range 18-88 years; 52% males) were included in the current study; 291 (50%) constituted indolent and 289 (50%) advanced variants; the latter included 85 (15%) ASM, 199 (34%) SM-AHN and 5 MCL cases. At presentation, anemia defined by hemoglobin level below the lower limit of the sex-adjusted reference range, was present in 41% of the patients, hemoglobin <10 g/dl in 16%, red cell transfusion-dependency in 9%, platelet count below the ROC-determined limit of 150 x 109/l in 26%, serum albumin below the lower normal limit (LNL) of the reference range in 22%, serum alkaline phosphatase (ALP) above the upper normal limit (UNL) of the reference range in 54%, urticaria pigmentosa in 41%, mast cell mediator symptoms in 46%, palpable hepatomegaly in 21%, palpable splenomegaly in 31%, “C” findings in 23% and “B” findings in 42%. Median follow-up was 34 months with 239 (41%) deaths and 9 (1.5%) leukemic transformations documented. Cytogenetic information was available in 342 cases, including 51 (15%) with abnormal karyotype and 27 (8%) with unfavorable karyotype. NGS-derived mutation information was available in 150 cases and most frequent mutations were KIT (75%), TET2 (29%), ASXL1 (17%) and CBL (11%).Age-adjusted multivariable analysis of clinical variables, which did not include mutation or cytogenetic information, identified age >60 years (HR 2.5, 95% CI 1.8-3.4), advanced vs ISM (HR 2.3, 95% CI 1.5-3.7), thrombocytopenia <150 x 109/l (HR 2.4, 95% CI 1.8-3.4), anemia (HR 2.1, 95% CI 1.5-3.0), ALP above UNL (HR 2.1, 95% CI 1.5-3.1) and albumin below LNL (HR 1.4, 95% CI 1.0-1.9). A similar age-adjusted multivariable analysis for mutations identified ASXL1 (HR 3.3, 95% CI 1.9-5.5), RUNX1 (HR 4.1, 95% CI 1.2-10.2) and NRAS (HR 5.7, 95% CI 1.7-14.9) as independent molecular risk factors; these mutations were henceforth labelled as “adverse”. The addition of “adverse” mutations (HR 2.7, 95% CI 1.6-4.7) to the list of the aforementioned clinical risk factors resulted in loss of significance for age and anemia while platelets below 150 x 109/l (HR 2.9, 95% CI 1.8-4.8), ALP above UNL (HR 3.2, 95% CI 1.8-6.1), albumin below LNL (HR 2.5, 95% CI 1.6-4.0) and advanced vs ISM (HR4.2, 95% CI 1.9-10.7) remained significant. Subsequently, based on the number of risk factors present, a “clinical” (figure 1a; n=380 informative cases) and “clinical-molecular” (figure 1b; n=129 informative cases) risk models were prepared; both risk models performed effectively for advanced and indolent SM, when analyzed separately (data not shown).Conclusions:The current study advances two separate but complimentary risk models for SM and illustrates the additional prognostic contribution of mutations and underlines the importance of thrombocytopenia and serum ALP and albumin levels in both risk models. Furthermore, we show effective application of both risk models in advanced and indolent SM. DisclosuresNo relevant conflicts of interest to declare.