Smoldering SM Research Articles

Development and Validation of a Diagnostic Tool for the Timely Diagnosis of Patients with Systemic Mastocytosis

Background: Systemic mastocytosis (SM), a rare, clonal mast cell disease associated with heterogenous clinical presentation, is characterized by severe, debilitating and often unpredictable skin, gastrointestinal, neurocognitive, and systemic symptoms (including life-threatening anaphylaxis), long-term co-morbidities, and in Advanced SM (AdvSM), organ damage due to mast cell infiltration. SM consists of 2 distinct groups of variants, advanced and non-advanced: AdvSM includes aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL); non-AdvSM includes indolent SM (ISM) and smoldering SM (SSM). Arriving at a definitive diagnosis may take years and is one of the challenges of SM management. To aid clinicians in the identification of SM, we developed and validated a diagnostic algorithm using data from select community hematology practices in the United States. Methods: A sample of 209 patients (SM and control) was obtained from the Quality Cancer Care Alliance (QCCA), a network of 19 community oncology and hematology practices. Data collection consisted of patient characteristics, laboratory parameters, and signs and symptoms at presentation. General linear models (GLM) with a logit link function were used in a backwards elimination process with the p value set at < 0.05 to identify patient factors at presentation that were associated with a diagnosis of SM. A Dx scoring algorithm (range: 0-26) was then derived from the final model coefficients, with the intent of correctly differentiating between SM and non-SM patients. A receiver operating characteristic (ROC) curve analysis was then done to measure the Dx accuracy of the algorithm. Results: Data from 105 SM and 104 non-SM control (diagnosed with hematological cancers) patients were collected from QCCA. The SM cohort included patients with different SM subtypes, including: ISM (47.6%); ASM (9.5%); SM-AHN (19.0%); MCL (1.9%); and subtype not documented (21.9%). The factors identified as being predictive ofa correct diagnosis of SM were 1) patient age, 2) lymph node status, 3) absolute neutrophil count, and 4-7) the following symptoms within 30 days of presentation: diarrhea, rash, skin lesions, and unintended weight loss. In the algorithm, patients were assigned scores for each diagnostic factor they possessed [Figure 1]. The final score was then associated with an overall percent likelihood of a positive SM diagnosis. The area under the ROC curve was 0.89 (95%CI 0.84-0.93), indicating good predictive accuracy. Patients with a total score of ≥ 9 units were found to be at highest risk for a positive SM diagnosis with the associated sensitivity, specificity, and positive predictive values of 84.8%, 76.0%, and 82.7%, respectively. Conclusions: This model indicates that the presence or absence of 7 characteristics may help determine whether patients are at increased risk of having SM. Use of this diagnostic algorithm may help facilitate earlier detection of SM by raising clinical suspicion to facilitate appropriate clinical workup, which would allow the timely initiation of effective targeted therapies for this rare disease. Additional application and external validation of the algorithm in a new sample of 162 patients managed through another community oncology network is ongoing.

Molecular and Cytogenetic Evaluation in Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare hematological neoplasm characterized by pleomorphic symptoms, related to mediators release from pathological mast cells. Tissue infiltration of liver, spleen, gastro-intestinal (GI) tract and osteolysis are present in aggressive disease. As KIT D816V mutation can be found in approximately 80% of patients, several additional somatic mutations of prognostic significance have been detected in a subset of patients. We report on clinical, cytogenetic and molecular characteristic of 160 patients with SM diagnosed in the last 15 years at our center. Fourteen (8.9%) patients had cutaneous mastocytosis, 85 (53.5%) had indolent SM (ISM), 12 (7.5%) had smoldering SM (SSM), 27 (17%) had aggressive SM (ASM), 17 (10.5%) had SM with an associated hematological neoplasm (AHN-SM) and 1 (0.6%) had mast cell leukemia. Symptoms were mostly related to mediators release: itching and blistering (69, 43%), anaphylaxis (49, 30%), diarrhea/bloating (19, 12%), osteoporosis/bone fracture (10, 6%), constitutional symptoms (8, 5%), bone pain and myalgia (16, 10%), anaphylaxis from Hymenoptera venom (24, 15%). While SM patients were mostly treated with antihistamines and membrane stabilizers, 29 patients needed a disease modifying therapy. Four patients with ISM were treated with Interferon (IFN) for bone lytic alterations, while 1 patient with ISM started midostaurin for uncontrolled symptoms. Other 11 patients with ASM were treated with midostaurin: 4 responded, while 7 needed multiple lines of therapy including allogeneic transplant in 4 cases. Eleven patients with ASM were treated with tyrosin kinase inhibitors (TKI) before midostaurin became available, while 2 elderly patients were treated with low dose cytarabine and TKI for concomitant acute leukemia. KIT D816V mutation was found in 111 of 131 (85%) evaluable patients with SM. Cytogenetics was normal in all but 2 patients with AHN-SM in which a chromosomal gain was reported. Among 6 patients with ISM, KIT mutation was found in only 2 cases. One patient had isolated KIT mutation and was treated with IFN for skin symptoms and bone fracture, and another patient had a DNMT3A associated mutation and was treated with imatinib. Moreover, 1 patient presented both DNMT3A and TET2 mutations and was treated with IFN for bone fracture. Among 12 ASM patients, 1 was negative for significant mutations: no disease control was achieved after target therapy, and bone marrow function slowly recovered after allogeneic transplant. The most frequently recorded mutations were SRSF2 and TET2: they were present in 4 patients each and recorded together in 3 cases. Two patients with SRSF2 and TET2 mutations died after multiple lines of therapy: 1 patient for infection and graft versus host disease after allogeneic transplant and 1 for progressive disease. Moreover, the latter had additional RUNX1 mutation. Two patients with concomitant SRSF2 and IDH1 mutations and TET2 mutation respectively responded to midostaurin, while 1 with DNMT3A mutation received multiple lines of therapy and died for pneumonia. One patient with ASXL1 mutation responded to chemotherapy after 2 previous lines of treatment. Among 4 patients with isolated KIT mutation, 2 responded to midostaurin, 1 obtained a partial control of symptoms after 4 lines of treatment and 1 suddenly died after achieving stable disease after 2 lines of therapy. Among 3 patients with SM associated to myelodyplastic syndrome, 1 was negative for KIT but positive for TP53 mutations and died for natural event after symptoms directed therapy and continuing recombinant erythropoietin. The other 2 KIT positive patients presented multiple concomitant mutations. Additional TET2 and SRSF2 mutations were recorded in a patient who died few weeks after diagnosis, while additional TET2, SRSF2, RUNX1 and KRAS mutations were recorded in a patient treated with midostaurine and 2CDA before successful allogeneic transplant. Molecular characterization of SM has uncovered a complex landscape of somatic mutations other than KIT D816V. Although the prognostic significance of some recurrent mutations has been reported, prospective correlation with clinical response may highlighted their role in the pathogenesis of disease and possibly elucidate mechanism of resistance to treatment. On the other hand, cytogenetics might no be considered mandatory except for AHN-SM

Initial Results from Summit: An Ongoing, 3-Part, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. Nonadvanced SM (NonAdvSM) includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). NonAdvSM is often associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preclinical studies demonstrate bezuclastinib inhibits KIT D816V with minimal brain penetration. Early results from Part 1 of a Phase 2 trial of patients with AdvSM demonstrate that bezuclastinib is well-tolerated and is associated with encouraging clinical activity. Bezuclastinib resulted in meaningful reductions in markers of disease burden including serum tryptase, bone marrow mast cell burden, and KIT D816V variant allele fraction (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). These results support the investigation of bezuclastinib as a potential therapy in NonAdvSM. Study Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, 3-part clinical trial of bezuclastinib in patients with NonAdvSM, including ISM and SSM, who have inadequate control of symptoms despite treatment with best supportive care (BSC). Patient-reported outcome measures (PROMs), including mastocytosis activity score (MAS) and mastocytosis quality of life (MC-QoL), are being used to assess treatment impact on symptoms and HRQoL. Approximately 48 patients will be enrolled in Part 1 of the trial with 1:1:1 randomization to one of two doses of bezuclastinib (100 or 200 mg QD for Part 1a; 100 or 150 mg QD for Part 1b) or placebo. Here we report initial data from Part 1a of the Summit trial. Results: Part 1a of Summit enrolled 20 patients; 18 patients had ISM and 2 patients had SSM. In Part 1a, a majority of patients were female (75%) and had an Eastern Cooperative Oncology Group Performance Status of 0-1 (90%) or 2 (10%). Mean age was 54. Patients utilized a median (range) of 3 (2 to 7) BSC medications, with 100% using H1 blockers, 95% using H2 blockers and 40% using leukotriene receptor antagonists. Enrolled patients had a median (range) serum tryptase of 74 (10 to 592) ng/mL and 85% of patients had a serum tryptase ≥20 ng/mL. 75% of patients were KIT D816V positive and median (range) KIT D816V variant allele fraction in whole blood was 0.5% (0 to 32). Median (range) percent bone marrow mast cell burden was 23% (1 to 80%). Utilizing MAS to assess baseline disease severity, a majority of patients self-reported severe disease with a median score of 43 (range 22-79). Patients also self-reported a mean score of 56+/- 19 on the MC-QOL, indicating moderate impact to their HRQoL. Conclusions: The Summit trial evaluating safety and efficacy of bezuclastinib enrolled 20 patients in Part 1a. The patients enrolled in Part 1a of the Summit trial are generally representative of the population of patients with moderate to severe nonadvanced systemic mastocytosis based on number of supportive care medications, symptom severity, and disease impact on HRQoL. Initial safety and efficacy results from Part 1a of the 3-part, randomized, double-blind, placebo-controlled Summit trial will be presented.

Incidence and Prevalence of Mastocytosis in Adults: A Danish Nationwide Register Study

Introduction: Mastocytosis is a heterogeneous chronic disease caused by a mutation in the cKIT gene that allows for uncontrolled proliferation, accumulation and activation of abnormal mast cells. Mastocytosis is divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM) in which abnormal mast cells are found in various tissues of the body. SM is further divided into the following five subtypes related to disease severity: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL). Mastocytosis is considered a rare disease with an incidence and prevalence previously found to be 0,89 per 100.000 and 9,59 per 100.000, respectively; however, recent improvements related to diagnostic methods could have led to an increased incidence and prevalence. Therefore, updated data is needed. Methods: This study is a retrospective nationwide register study including all adult (≥18 years) patients with mastocytosis in Denmark diagnosed between January 1 st 1997 and December 31 st 2021. The study was conducted using the Danish Civil Registration System to merge data from the National Patient Register (NPR), the Danish Pathology Register (DPR) and the Danish Cancer Register (DCR). The National Patient Register contain information on all inpatient and outpatient contacts and is considered complete as of 1995-2018. The Danish Pathology Register contain information about all biopsies and pathologic examinations in Denmark and is considered complete as of 1997 to 2021. The Danish Cancer Register contain information on all incidences of cancer in Denmark and is considered complete as of 1987-2021. Year of diagnosis was considered as the earliest date across all registers and patients were categorized as most severe subtype of mastocytosis. The registers did not allow for a categorization of SSM and therefore indolent mastocytosis were all categorized as ISM. Patients without a positive extracutaneous biopsy and who have never been examined with a bone marrow biopsy were classified as mastocytosis in the skin (MIS). Results: These data are the preliminary results of this study. 1627 patient were included (female 924, 56,8%). Mastocytosis in the skin was the most prevalent type of mastocytosis (774, 47,57%), followed by ISM (441, 27,11%), CM (222, 13,64%) and SM-AHN (179, 11%), More than 80% of patients with ASM had another hematologic neoplasm and were categorized as SM-AHN. Few patients were classified as ASM (4, 0,25%) and MCL (7, 0,43%). A positive bone marrow biopsy was found among 601 (36,94%) of the patients; however, 774 (47,57%) patients with mastocytosis were not examined with a bone marrow biopsy. The incidence rate of mastocytosis (all subtypes) was lowest in 2003 with an incidence of 0,74 per 100.000. Hereafter, the incidence increased until reaching the highest level in 2018 with an incidence of 2,77 per 100.000 (figure 1). The 25-year limited-duration prevalence as of 1 st January 2022 was 28,44 per 100.000. Conclusion: This nationwide register study provides updated data on the prevalence and incidence of mastocytosis in Denmark. The incidence rate was found to have an increasing trend until 2018 when it reached the highest value of 2,77 per 100.000. The prevalence was found to be 28,44 and thereby higher than previous studies have found. However, the true prevalence is potentially higher as the data for the years 2019-2021 solely relies on the pathology register. This is preliminary data, and the results will be updated when the NPR is complete for these years.Further analysis will be conducted using the Register of Laboratory Results for Research to evaluate blood tests regarding tryptase levels as well as to provide further information regarding KIT mutational status.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF©) and determination of a threshold score for moderate symptoms

BackgroundThe Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated.MethodsThe ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted.ResultsA total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable (α > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire (p < 0.01). A biweekly ISM-SAF TSS from 21 to 28 begins to distinguish the moderately to severely symptomatic ISM/SSM patients from mildly symptomatic patients.ConclusionThe biweekly TSS of ISM-SAF was reliable, construct-valid, and able to distinguish among clinically distinct groups. A cut-off value of 28 is a conservative threshold that can be used for screening purposes in future clinical studies to identify patients with at least a moderate severity of ISM symptoms.

Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Background: Systemic mastocytosis (SM) is characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. NonAdvSM is characterized by the lack of mast cell-related organ damage (e.g., C-findings) and other features of advanced SM such as associated hematologic neoplasms. NonAdvSM includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). ISM affects nearly 85% of the general SM population and is characterized by symptoms related to mast cell degranulation/mediator release. SSM is characterized by higher mast cell burden in the absence of organ damage or an associated hematologic neoplasm. There are currently no approved therapies for the treatment of the underlying causes of ISM or SSM, and anti-mediator therapies are used for symptom control with variable efficacy and tolerability due to disease heterogeneity. In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17; therefore, agents targeting this mutated kinase have been used to treat advanced SM variants. However, off-target activity of these agents may lead to toxicities that limit dosing and thus efficacy in this population. Therefore, an unmet need remains for safe and effective treatments for patients with NonAdvSM. Bezuclastinib inhibits KIT D816V mutations with high potency and specificity while avoiding other kinases with potential off-target liabilities such as PDGFRα, PDGFRβ, VEGFR2, and CSF1R. Bezuclastinib has demonstrated minimal brain penetration and no central nervous system toxicities were observed in preclinical studies. In an ongoing Phase 2 study (Apex) of patients with AdvSM, early data indicate that bezuclastinib was generally well tolerated and is associated with a meaningful reductions in serum tryptase levels, bone marrow mast cell burden, and KIT D816V variant allele fraction. Additionally, bezuclastinib was safely administered in a completed phase 1/2 clinical study in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST), in which activating KIT mutations are found in a majority of patients. In that study, bezuclastinib led to a reduction in KIT exon 17 mutational burden, which was associated with a reduction in tumor burden. These results support the investigation of bezuclastinib as a potential therapy in GIST as well as AdvSM and NonAdvSM. Study Design and Methods: The Summit study (NCT05186753) is a multi-center, Phase 2, double-blind, placebo-controlled, 3-part clinical trial to evaluate the safety, efficacy, and biomarker correlates (e.g., bone marrow mast cell burden, serum tryptase level, and KIT D816V mutation burden) of bezuclastinib in patients with NonAdvSM. Patients diagnosed with ISM or SSM who have inadequate control of their symptoms despite treatment with at least 2 anti-mediator therapies will be included in this trial. Multiple patient-reported outcome measures (PROMs) will be used to follow symptom scores while on treatment. Part 1 of the study will assess the safety profile of bezuclastinib and will determine the recommended dose for Part 2 through the assessment of changes from baseline of a disease specific PROM. Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo through the evaluation of the PROMs and changes in clinical activity markers such as serum tryptase, bone marrow mast cell burden, and KIT D816V mutation allele burden. All patients will continue to receive their baseline anti-mediator treatments throughout the trial. Serial photographic evaluation will assist in the determination of changes of disease in the skin. Part 3 allows patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, to participate in a long-term extension study and receive open label bezuclastinib. Conclusions: There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Midostaurin therapy for indolent and smoldering systemic mastocytosis: Retrospective review of Mayo Clinic experience

Midostaurin therapy for indolent and smoldering systemic mastocytosis: Retrospective review of Mayo Clinic experience

A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF\xa9

BackgroundAdvanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis.MethodsA review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated.ResultsFor AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients.ConclusionThe AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients’ perspective.

The Role of Avapritinib for the Treatment of Systemic Mastocytosis.

Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.

Mastocytosis in the skin accompanied by pseudo-Kaposi's sarcoma.

Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of neoplastic mast cells in the skin and/or other extracutaneous tissues. Most patients with skin involvement can be subclassified into one of the three subtypes of cutaneous mastocytosis currently recognized by the World Health Organization (i.e., mastocytoma, maculopapular cutaneous mastocytosis and diffuse cutaneous mastocytosis); however, some patients may occasionally present with atypical skin lesions that cannot be ascribed to any of these disease subtypes. Here, we report three patients diagnosed with mastocytosis and an unusual cutaneous involvement mimicking Kaposi's sarcoma. Skin biopsies showed neoplastic mast cell infiltrates together with features commonly seen in acroangiodermatitis, and immunohistochemistry for human herpesvirus 8 was negative. One patient fulfilled the criteria for aggressive systemic mastocytosis, showed no response to cytoreductive therapy, and died because of disease progression. The remaining two patients had indolent and smoldering systemic mastocytosis, respectively, but they showed several features associated with an unfavorable prognosis such as extensive involvement of the hematopoiesis by the KIT D816V mutation, increased serum β2-microglobulin, and decreased serum lactate dehydrogenase. The presence of pseudo-Kaposi's sarcoma skin lesions is an uncommon finding in mastocytosis which may alert physicians to the possible existence of underlying features indicative of a poor prognosis.

Substitution of opioids by N-methyl-D-aspartate receptor antagonists for treating pain in mastocytosis

Mastocytosis is a spectrum of rare diseases characterized by mast cell accumulation in 1 or more organs. It is classified into the following 3 main groups: cutaneous mastocytosis; systemic mastocytosis (SM); and mast cell sarcoma.1 The following 5 major SM variants have been defined: indolent SM, smoldering SM (SSM), SM with an associated hematologic neoplasm, aggressive SM, and mast cell leukemia.

Laboratory Tests in Diagnosis of Mastocytosis: Literature Review and Case Report

Abstract Мastocytosis is a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs) in the skin and/or other organ systems. Mastocytosis is a rare disease. The annual incidence is 5-10 cases per 1 million people. However, the majority of cases stay undiagnosed due to the lack of specific tests and a wide variety of clinical features of the disease. In mastocytosis, somatic mutations of KIT gene lead to autocrine dysregulation and constitutive c-KIT activation in the absence of its ligand SCF. Clinical symptoms of the disease are determined by MC mediator release and/or infiltration of tissues by MCs. According to the World Health Organisation classification updated in 2016 mastocytosis is divided to cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), SM with an associated hematologic (non-MC-lineage) neoplasm (SMAHN), aggressive SM (ASM), MC leukemia (MCL) and MC sarcoma (MCS). The CM and ISM prognosis is excellent with (almost) normal life expectancy, unlike aggressive forms (ASM and MCL) with poor prognosis. In this paper the key aspects of clinical features and diagnostic criteria of mastocytosis are discussed. We present a case report of a patient with mastocytosis in the skin following psoralen plus ultraviolet A (PUVA) therapy with good response.

PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis (SM) With Symptoms Inadequately Controlled by Standard Therapy

PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis (SM) With Symptoms Inadequately Controlled by Standard Therapy

Pioneer: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy

Pioneer: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy

UK Single Institution Experience of Mastocytosis: Guy's and St Thomas' NHS Foundation Trust

Introduction: Systemic mastocytosis (SM) is a heterogeneous disorder of neoplastic mast cells ranging from an indolent to aggressive multi-system disease. We registered our UK Mastocytosis Centre of Excellence with the European Competence Network of Mastocytosis (ECNM) in 2005. Our multidisciplinary team (MDT) includes haematologists, haematopathologists, dermatologist, immunologist and molecular diagnosticians. Over 500 patients have been reviewed in our quarterly SM-MDT. We present a large single centre experience of a rare disorder. Method: We have reviewed prospective and retrospectively collected clinical data for 125 adult patients from 2009. The data captures clinical, laboratory, diagnostic results and management. Local patients with a tryptase level of &gt;20ug/L are offered haematology review and bone marrow investigation with KIT D816V mutation analysis using digital PCR. Patients seen for a second opinion have their diagnostic material reviewed. Since 2018, next generation sequencing (NGS) based myeloid gene panels are carried out on patients with advanced SM (AdvSM). Results: Classification of mastocytosis patients: In 125 patients no gender bias was seen: 56 (44.8%) were male and 69 (55.2%) female. Median age of patients with indolent SM (ISM) was 49 years (range 22-78); and for AdvSM: (aggressive SM, SM with an associated haematological neoplasm and mast cell leukaemia) was 64years (range 5-77). The median serum tryptase level was 48.9ug/L for ISM patients (range 4-682) and 120ug/L for AdvSM patients (range 24-854). 112/125 patients had a bone marrow biopsy. 13 patients chose not to have a biopsy. 88% (110/125) of patients had a mast cell disorder. 4% (5/125) had no marrow involvement. 84% (105/125) met WHO criteria for a diagnosis of SM - Figure 1.These were sub-classified: 71/105 (67%) ISM; 2/105 (2%) smouldering SM (SSM); 3/105 (3%) aggressive SM (ASM); 2/105 (2%) mast cell leukaemia (MCL) and 27/105 (26%) SM with an associated hematologic neoplasm (SM-AHN). The most frequent associated haematological neoplasms were MPN and CMML. Lymphomas (n=3) and plasma cell dyscrasias (n=1) were seen patients. In 10/27 (37%) cases of SM-AHN the SM was the initial diagnosis with subsequent development of an AHN. In 5/27(19%) cases the AHN component preceded the SM and in 12/27 (44%) cases the 2 components were co-diagnosed. Mutation status : 24/32 patients with AdvSM were noted to be positive for an activating KIT mutation (D816V, n=23; D816L, n=1). 15/32 AdvSM patients had NGS myeloid gene panel analysis for the SAR panel (SRSF2, ASXL1 and RUNX1) which confers poor prognosis. 4 of the15 patients harboured at least 2 out of 3 SAR mutations. JAK2 V617F mutation was detected in 7 of 8 classical MPN patients and in 1 of 4 patients with MPNu/MDS overlap. 4 patients had a TET2 mutation. 1 patient with mast cell leukaemia had a GATA2 mutation in addition to all 3 in the SAR panel. Cutaneous involvement: 70% (88/125) of patients had skin involvement: 62% (78/125) urticaria pigments, 3% (4/125) telangiectasia macularis eruptiva perstans and 5% (6/125) having non-specific involvement. Skin involvement was more common in ISM (78%) than AdvSM (54% in SM-AHN, none in the 2 patients with MCL). Management : Treatments in ISM are usually for symptom control. Antihistamines, anti-inflammatory agents, anti-leukotriene agents, mast cell stabilising agents, bisphosphonates, proton-pump inhibitors, PUVA and steroids are used. Various cytoreductive therapies have been used in AdvSM (hydroxycarbamide, pegylated interferon-α, cladrabine, cytarabine, azacitadine alone/combination with midostaurin). Patients with SM-AHN have tailored management depending on the disease component that requires treatment. Access to targeted therapies for AdvSM patients in a trial or compassionate use programme has been successful: 7/32 patients with advanced SM have been enrolled into trials (midostaurin 1; avapritinib 6). Conclusions: Our data reflects the heterogeneous nature of the SM classification spectrum clinically and diagnostically. An experienced MDT provides holistic high standard of care within a comprehensive centre for good patient outcomes (Figure 2). Development of a portfolio of novel therapeutic options in multi-centred, international collaborative trials is beneficial to patients and pivotal for research in this rare disorder. Disclosures Cross: Novartis: Consultancy, Research Funding; Incyte: Consultancy. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. OffLabel Disclosure: There are very few medications available in mastocytosis and various off label medications have been used including pegylated interferon alpha.

Magnetic resonance imaging reveals distinct bone marrow patterns in indolent and advanced systemic mastocytosis.

Systemic mastocytosis (SM) is broadly subcategorized according to mast cell (MC) burden and organ involvement into indolent (ISM), smoldering (SSM), and advanced SM (AdvSM). However, the pattern and extent of bone involvement remains controversial. In this institutional review board (IRB)-approved study, 115 patients with different forms of SM (ISM (n= 37, 32%), SSM (n= 9, 8%), and AdvSM (n= 69, 60%)) underwent a whole-body magnetic resonance imaging including sagittal and coronal T1 and turbo inversion recovery magnitude (TIRM) sequences of the spine. The evaluation included the pattern and extent of pathologic bone marrow (BM) signals in the spine and extremities, osteolytic lesions, and vertebral fractures. A pathologic BM pattern was observed in 4/37 (11%), 8/9 (89%), and 66/69 (96%); affection of the appendicular skeleton in 3/37 (8%), 8/9 (89%), and 67/69 (97%); and vertebral fractures in 7/37 (19%), 0/9, and 13/69 (19%) patients with ISM, SSM, and AdvSM, respectively. In AdvSM, pathologic BM pattern included activated (62%), diffuse sclerotic (25%), and small-spotted BM (9%), respectively. Only activated/sclerotic BM was associated with significantly higher MC burden, organ damage, and inferior median survival (2.9years, p= 0.04). Vertebral fractures resembled classical multi-segmental osteoporotic fractures in ISM but not in AdvSM in which they were only found in activated/sclerotic BM. Only one patient with AdvSM had a focal osteolytic lesion in the femur. Activated/sclerotic BM changes of the spine and affection of the appendicular skeleton are indicative for SSM or AdvSM. Osteolytic lesions, which are very rare, and osteoporotic fractures are ineligible for the diagnosis of AdvSM.

Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM): Analyses of Patient Reported Outcomes (PROs) from the Phase 1 (EXPLORER) Study Using the (AdvSM) Symptom Assessment Form (AdvSM-SAF), a New PRO Questionnaire for (AdvSM)

Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM): Analyses of Patient Reported Outcomes (PROs) from the Phase 1 (EXPLORER) Study Using the (AdvSM) Symptom Assessment Form (AdvSM-SAF), a New PRO Questionnaire for (AdvSM)