Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin

Abstract Background: Advanced systemic mastocytosis (AdvSM) comprises a group of hematologic neoplasms primarily driven by the oncogenic KIT D816V mutation. Morbidity and mortality relate to organ damage caused by neoplastic mast cell infiltration and mast cell mediator symptoms. Midostaurin, an oral multikinase/KIT inhibitor, produced reversion of organ damage in 60-70% of AdvSM patients (Gotlib et al, NEJM, 2016; DeAngelo et al, Leukemia, 2018), which was associated with decreases in bone marrow mast cell burden, serum tryptase levels, and splenomegaly in the majority of patients. Similar to myelofibrosis (MF) patients treated with JAK inhibitors, midostaurin improves disease symptoms and quality of life (Gotlib et al, NEJM, 2016). We conducted a cytokine profiling study to better understand the biologic effects of midostaurin in this patient population. Methods: Plasma cytokine levels were analyzed in 19 patients with AdvSM (2 aggressive SM, 10 SM with an associated hematologic neoplasm, and 7 with mast cell leukemia) treated with midostaurin 100 mg twice daily. Seventeen patients were treated on the phase II investigator-initiated trial (DeAngelo et al,Leukemia, 2018), and two were treated on a compassionate-use basis. Cytokine levels were compared to 10 patients with MF (primary MF [n=4]; post PV/ET MF [n=6]), treated with JAK inhibitors (ruxolitinib, fedratinib, or momelotinib) and 10 healthy patients whose age range matched the SM group. Plasma samples were obtained pretreatment, and after 4-8 weeks of therapy. Each patient sample was evaluated for 62 cytokines using a Luminex assay (eBioscience) performed at the Stanford Human Immune Monitoring Center. Sparse partial least squares discriminant analysis (SPLS-DA) was used to identify the most predictive cytokines from the expression data that help classify patient samples based on disease states, and SPLS regression was used to identify cytokines correlated with survival (Rohart et al, mixOmics. R package version 6.3.2). Overall survival was calculated from the time of initiation of midostaurin to time of death. Results: Plasma levels of several cytokines were higher at baseline in AdvSM and MF patients compared to healthy controls (Fig 1A-B). In patients with AdvSM and MF, pretreatment levels of leptin (false discovery rate (FDR) < 0.002), epidermal growth factor (EGF; FDR < 2e-5), and brain-derived neurotrophic factor (BDNF; FDR < 3.5e-7) were lower than healthy controls. Using SPLS-DA, we identified a distinct baseline cytokine expression profile that could classify patient samples as either AdvSM, MF, or healthy with an error rate of less than 0.10 (Fig 1C). The six most predictive cytokines were nerve growth factor, EGF, BDNF, interferon alpha, intercellular adhesion molecule-1 (ICAM1), and leukemia inhibitory factor. Corroborating prior data (Verstovsek et al, NEJM 2010), we found that several plasma cytokine levels significantly decreased in MF patients after 1-2 cycles of JAK inhibition (Fig 1B). Although we observed similar decreases in plasma cytokine levels for AdvSM patients on midostaurin (Fig 1A), the results were more variable and did not reach statistical significance. AdvSM patients that responded to midostaurin (major or partial response per Valent criteria) expressed a different baseline cytokine expression profile when compared to non-responders. SPLS-DA was able to distinguish these two classes of patients with an error rate of 0.35 (Fig 1D). SPLS regression identified baseline levels of interleukin-7 (IL7), ICAM1, interleukin 12 subunit p40 (IL12p40), EGF, and platelet-derived growth factor BB (PDGFBB) as potential predictors of survival for patients with AdvSM treated with midostaurin. High pretreatment levels of IL7 (109 months (m) vs. 33 m; p=0.01), EGF (92 m vs. 34 m; p=0.04), and PDGFBB (80 m vs. 37 m; p=0.09) and low pretreatment levels of ICAM1 (91 m vs. 19 m; p=0.02) and IL12p40 (91 m vs. 19 m; p=0.03) were associated with increased survival. Conclusions: Cytokine expression profiling can distinguish patients with AdvSM or MF from healthy controls. Compared to the use of JAK inhibitors in MF, midostaurin's activity in AdvSM appears less related to reversion of pro-inflammatory cytokines. Investigation of a larger cohort of patients is needed to determine whether such analyses of plasma cytokines will provide added value to new scoring prognostic systems of AdvSM that incorporate clinical and molecular data. Disclosures DeAngelo: Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Takeda: Honoraria; BMS: Consultancy; Incyte: Consultancy, Honoraria; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding. George:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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Midostaurin (PKC412) Demonstrates a High Rate of Durable Responses in Patients with Advanced Systemic Mastocytosis: Results from the Fully Accrued Global Phase 2 CPKC412D2201 Trial

Blood ◽

10.1182/blood.v124.21.636.636 ◽

2014 ◽

Vol 124 (21) ◽

pp. 636-636 ◽

Cited By ~ 5

Author(s):

Jason Gotlib ◽

Hanneke C. Kluin-Nelemans ◽

Tracy I. George ◽

Cem Akin ◽

Karl Sotlar ◽

...

Keyword(s):

Mast Cell ◽

Research Funding ◽

Systemic Mastocytosis ◽

Organ Damage ◽

High Rate ◽

Advisory Committees ◽

Laboratory Services ◽

Grade 3 ◽

Stage 1 ◽

Kit D816v

Abstract Background: Patients (pts) with advanced systemic mastocytosis (SM), including aggressive SM (ASM) and mast cell leukemia (MCL) ± associated clonal hematologic non–mast cell lineage disease (AHNMD), have a poor prognosis with few effective treatment options. More than 80% of pts express the activating KIT D816V mutation. The oral multikinase inhibitor midostaurin inhibits wild-type and D816-mutated KIT. In this global phase 2 trial (NCT00782067), the largest prospective trial in advanced SM, a planned interim analysis of stage 1 pts demonstrated a high overall response rate (ORR) with reductions in marrow mast cell (MC) burden and a favorable safety profile (Gotlib et al, Blood 2012). Updated stage 1 results showed improvements in symptoms and quality of life (QOL) (Gotlib et al, Blood 2013). Here, we report primary results for the fully accrued trial. Methods: This single-arm trial consisted of an adapted Fleming 2-stage design. Midostaurin 100 mg twice daily was administered in continuous 28-day cycles until progression or unacceptable toxicity. Eligibility and responses (modified from Valent et al,Leuk Res 2003) were adjudicated by study steering committee (SSC). Histopathology was centrally assessed. Eligible pts had ≥ 1 measurable C-finding (CF) defined as SM-related organ damage. The primary endpoint was ORR (major response [MR] + partial response [PR]) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). Results: Of 116 enrolled pts, 89 (77%) were eligible for efficacy evaluation; pts were considered ineligible by the SSC due to absence of measurable CF (n = 14) or organ damage considered unrelated to SM (n = 13). Median age was 64 years (range 25-82). Overall, 73 pts (82%) had ASM, including 57 (78%) with an AHNMD (ASM-AHNMD); 16 (18%) had MCL, including 6 (38%) with an AHNMD (MCL-AHNMD). AHNMDs included chronic myelomonocytic leukemia (n = 25), myelodysplastic/myeloproliferative neoplasm unclassifiable (n = 22), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL; n = 5), and 11 other subtypes. A total of 37 pts (42%) had received ≥ 1 prior therapy (median 1; range 1-4). Seventy-seven pts (87%) were positive and 10 pts (11%) were negative for KIT D816V/Y/L mutation; 2 pts were not evaluable. The ORR was 60% (53/89); most responses were MRs (40/53, 75%), subtyped as incomplete remission (IR) in 36%, pure clinical response in 28%, and unspecified in 11%. PRs included good PR (GPR) in 21% and minor PR in 4% of pts. Overall, 12%, 11%, and 17% of pts had stable disease, progressive disease, or were not evaluable for response, respectively. After a median follow-up of 26 months (mo; range 12-54), the median duration of response (DOR) and median overall survival (OS) were 24.1 and 28.7 mo, respectively (Figure). Median OS in responders was 44.4 mo. Of 16 MCL pts, 8 responded, including 7 MRs (44%); median DOR was not reached (NR), with 3 IRs ongoing (49+, 33+, and 19+ mo). Median OS was 9.4 mo among all pts with MCL and NR among responders. Median change in MC burden in 72 evaluable pts was -59% (range -96% to 160%); 41 pts (57%) had ≥ 50% reduction. Median best change in serum tryptase level in 89 evaluable pts was -58% (range -99% to 185%); 32 pts (36%) had ≥ 50% reduction lasting ≥ 8 wk. Four of 5 responding ASM/MCL-HES/CEL pts (1 IR, 3 GPR) also had complete resolution of eosinophilia (mean % and absolute eosinophils at baseline: 57% and 12.4 × 109/L). Improvements in symptoms and QOL were consistent with those reported previously (Gotlib et al, Blood 2013). All 116 pts received ≥ 1 midostaurin dose and were evaluable for safety. Grade 3/4 drug-related hematologic adverse events (AEs) were neutropenia (5%), leukopenia (4%), febrile neutropenia (3%), anemia (3%), and thrombocytopenia (3%). Low-grade nausea was common but usually manageable with antiemetics. The most frequent grade 3/4 drug-related non-hematologic AEs included nausea (6%), vomiting (6%), fatigue (4%), and increased lipase/amylase (4%/3%). As of July 9, 2013, 65 pts had discontinued therapy, most commonly due to progression (n = 31) and AEs (n = 18; 11 were considered drug related [3 hematologic and 8 non-hematologic AEs]). Seven patients developed acute myeloid leukemia related to a prior AHNMD. Conclusions: Midostaurin exhibits a high rate of durable responses in pts with advanced SM, particularly in MCL, which has a dismal prognosis. The reductions in MC burden suggest that midostaurin may impact the natural history of the disease. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Gotlib: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Support Other. George:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Novartis Pharma: Laboratory Services, Laboratory Services Other; Nanostring Technologies: Consultancy. Hermine:Novartis: Research Funding. Awan:Boehringer Ingelheim: Consultancy; Lymphoma Research Foundation: Research Funding. Mauro:Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Oncology: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Sternberg:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Villeneuve:Novartis Pharma AG: Employment. Emery-Salbert:Novartis: Employment. Stanek:Novartis Pharmaceuticals Corporation: Employment. Hartmann:Novartis: Consultancy. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding. Reiter:Novartis: Consultancy, Honoraria.

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Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants

Blood ◽

10.1182/blood-2021-145082 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2567-2567

Author(s):

Emily C. Liang ◽

Cecelia Perkins ◽

Rong Lu ◽

Justin Abuel ◽

Cheryl Langford ◽

...

Keyword(s):

Clinical Trials ◽

Mast Cell ◽

Board Of Directors ◽

Research Funding ◽

Systemic Mastocytosis ◽

Organ Damage ◽

Initial Presentation ◽

Pleural Effusions ◽

Advisory Committees ◽

Significant Difference

Abstract BACKGROUND: Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in various organs, including the bone marrow, liver, spleen, and gastrointestinal tract. Advanced SM (AdvSM) comprises 3 subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Individuals with AdvSM often exhibit hematologic and/or non-hematologic organ damage (C-findings), which contributes to the poor prognosis of these patients (pts). To date, the presenting patterns of organ damage across the spectrum of AdvSM subtypes have not been well characterized. In addition, the definition of hematologic and non-hematologic organ damage has evolved from the initial characterization of C-findings used by the World Health Organization (WHO) to define ASM, to more clinically relevant and quantifiable organ damage criteria that are used to assess eligibility for clinical trials in AdvSM. These include the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG) criteria and a modified version of these criteria (mIWG), which differ slightly regarding splenomegaly (IWG: symptomatic splenomegaly >5 cm; mIWG: spleen >5 cm). In this retrospective analysis, we describe the distribution and frequency of organ damage at the time of initial presentation among the 3 subtypes of AdvSM as defined by WHO, IWG, and mIWG criteria. METHODS: Among 251 pts with mast cell disorders in our Stanford IRB-approved MPN registry, we identified 87 AdvSM pts between October 1999 and September 2020. Thirteen pts (15%) had ASM, 63 (72%) had SM-AHN, and 11 (13%) had MCL. Comparisons between continuous and categorial variables were performed using the Kruskal-Wallis test and the Fisher's exact test, respectively. We defined IWG/mIWG liver-associated organ damage as a composite of ascites/pleural effusions requiring diuretics or drainage, liver function abnormalities, and/or hypoalbuminemia. RESULTS: Median age at diagnosis was 64 years (range 24-88) and 55 pts (63%) were male. The median number of prior treatments was 1 (range, 0-4). Forty-six pts (53%) were enrolled on clinical trials, and they had a median of 2 organ damage findings by WHO or IWG/mIWG criteria. ASM, MCL, and SM-AHN pts had significantly different WBC, ANC, and monocyte counts; pts with SM-AHN had the highest median white blood cell count (11.4 x 10 9/L), absolute neutrophil count (5.69 x 10 9/L), and monocytosis (1.58 x 10 9/L). Pts with SM-AHN exhibited a trend towards a higher absolute eosinophil count compared to ASM pts (p = 0.06). There was a significant difference in IWG/mIWG-defined RBC and platelet transfusion dependence in the 12 weeks prior to initial presentation. Pts with MCL had the highest transfusion requirement, with 55% and 27% of pts requiring red blood cell and platelet transfusions, respectively. There were no differences in median hemoglobin, platelet count, liver function tests, serum albumin, pleural effusions/ascites, and liver or spleen size by palpation or volumetric imaging. Across the 3 AdvSM subtypes, a significant difference was observed between the # of pts fulfilling IWG/mIWG criteria for liver-related organ damage (p = 0.044). Pts with SM-AHN (p = 0.071) and MCL (p = 0.013) fulfilled more IWG/mIWG liver criteria compared to ASM pts. While the absolute number of IWG/mIWG non-hematologic organ damage findings was not different across the 3 subtypes, a pairwise comparison revealed a statistically higher number of IWG non-hematologic organ damage findings in MCL vs. ASM. Irrespective of the criteria, there were no significant differences in organ damage between pts receiving 0, 1, or ≥2 prior therapies. CONCLUSION: We provide a preliminary snapshot of the patterns of WHO and IWG/mIWG-defined organ damage at initial presentation across a spectrum of AdvSM pts. Pts with MCL had the highest transfusion requirements, and liver-associated organ damage appears to be more frequent in SM-AHN and MCL pts compared to ASM. We next plan to study the profile of organ damage using WHO, IWG, and mIWG criteria in AdvSM patients who enrolled on the phase I (NCT02561988) and phase II (NCT03580655) studies of avapritinib. These analyses will include clinicopathologic and genetic correlates of organ damage, including # prior therapies, KIT D816V variant allele frequency, and myeloid mutation profile. Disclosures Shomali: Incyte: Consultancy, Research Funding; Blueprint Medicines: Consultancy. Gotlib: Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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An Increased Bone Mineral Density As an Adverse Prognostic Factor in Patients with Systemic Mastocytosis

Blood ◽

10.1182/blood-2019-129798 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4185-4185

Author(s):

Mohamad Jawhar ◽

Juliana Schwaab ◽

Nicole Naumann ◽

Georgia Metzgeroth ◽

Alice Fabarius ◽

...

Keyword(s):

Bone Mineral Density ◽

Mast Cell ◽

Research Funding ◽

Systemic Mastocytosis ◽

Organ Damage ◽

Z Score ◽

Serum Tryptase ◽

Mineral Density ◽

T Score ◽

Bone Marrow Mast Cell

Systemic mastocytosis (SM) is characterized by expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) and advanced SM (AdvSM). ISM patients usually present with a low mast cell burden and have a nearly normal life expectancy while AdvSM patients have a high disease burden, multiple organ damage and poor prognosis. In ISM patients, measurement of the bone mineral density (BMD) frequently reveals osteopenia and osteoporosis (lumbar spine BMD T-score of ≤ −2.5 standard deviation [SD]). In contrast, the association between increased BMD and osteosclerosis, respectively, and the various SM subtypes is unclear. We therefore sought to evaluate the BMD in 61 patients (ISM, n = 29, 48%; AdvSM, n = 32, 52%) and correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters and prognosis. All patients were scanned on the same 16 row CT Scanner (SOMATOM Emotion 16, Siemens Healthcare Sector, Forchheim, Germany). The results were expressed as T-score (SD below the mean of young healthy adults) and as Z-score (SD below the age- and gender-matched mean reference value). According to established WHO criteria, osteoporosis was defined as a lumbar spine BMD T-score of ≤ −2.5 SD. Increased BMD and osteosclerosis were defined as Z-score > 1 SD and > 2 SD, respectively. Osteoporosis was detected in 11/29 (38%) patients with ISM and 2/32 (6%) patients with AdvSM (p = 0.004). Bone marrow mast cell infiltration (median 10% versus 20%, p=0.035) and serum tryptase levels (median 31 µg/L versus 58 µg/L, p = 0.047) were significantly lower in ISM patients with osteoporosis as compared to those without osteoporosis (n=18, 62%). No significant differences were seen regarding age, gender, blood counts, and overall survival. An elevated BMD was detected in 1/29 (3%) patient with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD were older (median 77 years versus 68 years, p = 0.0043), had lower platelet counts (median 111 x 109/L versus 238 x 109/L, p = 0.041) and higher levels of bone marrow mast cell infiltration (50% versus 10%, p=0.002), serum tryptase (median 262 µg/L versus 62 µg/L, p = 0.003) and alkaline phosphatase (238 U/L versus 74 U/L, p < 0.0001). In consequence, prognosis of AdvSM patients with increased BMD was significantly inferior as compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). In conclusion, i) osteoporosis is a common feature in ISM but not in AdvSM patients, ii) an increased BMD is frequent in AdvSM but not in ISM patients, iii) osteosclerosis is restricted to AdvSM patients, and iv) an elevated BMD is associated with a more aggressive phenotype and inferior survival (Figure A-B). Disclosures Fabarius: Novartis: Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement.

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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)

Blood ◽

10.1182/blood-2021-147072 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3642-3642

Author(s):

Frank Siebenhaar ◽

Jason Gotlib ◽

Michael W. Deininger ◽

Daniel J. DeAngelo ◽

Francis Payumo ◽

...

Keyword(s):

Mast Cell ◽

Board Of Directors ◽

Research Funding ◽

Systemic Mastocytosis ◽

Symptom Burden ◽

Phase 2 ◽

Advisory Committees ◽

Management Committee ◽

Study Management ◽

Kit D816v

Abstract Systemic mastocytosis (SM) is characterized by mast cell infiltration of ≥ 1 extracutaneous organs and encompasses a spectrum of diagnoses that can range from a non-advanced to advanced disease (Shomali et al, 2018). There are two nonadvanced variants of SM: indolent systemic mastocytosis (ISM), which accounts for approximately 85% and smoldering systemic mastocytosis (SSM), which includes about 5% of the general SM population (Cohen et al, 2014, Jennings et al, 2014). ISM is characterized by 0 or 1 B-findings and SSM by 2 or more B findings and absence of organ damage or an associated hematologic neoplasm (Gotlib et al, 2018). There are currently no approved therapies to treat the underlying disease of ISM or SSM. Although anti-mediator therapies (e.g. anti-H1 and H2 antihistamines, leukotriene receptor antagonists, cromolyn sodium, corticosteroids) are used to control symptoms such as anaphylaxis, GI intolerance, and flushing to improve quality of life, their effectiveness and tolerability are variable. Many patients experience a persistently high symptom burden despite maximized anti-mediator therapies. Because the molecular pathogenesis of SM is driven by KIT D816V mutations in 95% of patients (Garcia-Montero et al, 2006, Jara-Acevedo et al, 2015, Vaes et al, 2017), other agents targeting this mutated kinase have been used to treat the spectrum of SM variants; however, toxicities such as cognitive impairment, GI effects, intracranial hemorrhage, and edema may limit dosing and thus efficacy. In addition to targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Furthermore, bezuclastinib has demonstrated minimal brain penetration and no CNS toxicities have been identified in preclinical studies. Preliminary clinical activity with bezuclastinib has been observed in patients with advanced solid tumors or locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST). A reduction in KIT exon 17 mutational burden was observed in patients treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). This is a multi-center, Phase 2, double blind, placebo-controlled, 3-part clinical study to evaluate the safety, efficacy, and biomarker correlates (e.g. bone marrow mast cell percentage, serum tryptase level, and KIT D816V mutation burden) of the KIT inhibitor bezuclastinib in patients with ISM and SSM. This study will enroll patients with SSM and moderate-to-severe ISM who have inadequate control of their symptoms despite at least 2 anti-mediator treatments. Part 1 of the study is intended to determine the recommended dose of bezuclastinib in Part 2. Subjects will be randomized to placebo or 1 of 3 doses of bezuclastinib which will be administered in combination with a baseline regimen of best supportive care (BSC). Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo. Efficacy will be measured by the reduction of symptom burden as assessed by the mastocytosis activity score (MAS), a disease specific patient reported outcome tool (Siebenhaar et al, 2018). In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, may participate in a long-term extension and receive open-label bezuclastinib in combination with BSC. The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM. Disclosures Gotlib: Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deininger: Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees. DeAngelo: Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Mensing: Cogent Biosciences, Inc.: Current Employment. Jolin: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. George: Bristol Meyers Squibb: Consultancy; Blueprint Medicines: Consultancy; Celgene: Consultancy; Incyte Corporation: Consultancy. OffLabel Disclosure: study of investigational agent

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Burden of Illness of Aggressive Systemic Mastocytosis (ASM)

Blood ◽

10.1182/blood.v118.21.4755.4755 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4755-4755

Author(s):

Michelle L Sotak ◽

Mihaela Marin ◽

John Coombs ◽

April Teitelbaum

Keyword(s):

Mast Cell ◽

Resource Utilization ◽

Research Funding ◽

Systemic Mastocytosis ◽

Indirect Costs ◽

Direct Costs ◽

Annual Incidence ◽

Population Projections ◽

The Us ◽

And Gender

Abstract Abstract 4755 Introduction: Per the 2008 WHO report on the spectrum of mast cell disease, ASM is a severe and debilitating form that may progress to mast cell leukemia. Very little has been published on the epidemiology and burden of ASM. This study reviewed the epidemiologic, clinical, humanistic and economic literature on ASM in order to estimate the burden of ASM in the US. Methods: A systematic literature review was conducted in PubMed to identify publications regarding ASM published in English from 2000 to 2011. Data relevant to the burden of ASM were abstracted. 181 citations were identified in PubMed. 156 abstracts were screened and 6 articles were abstracted. An Excel model was developed to estimate the population-level burden of ASM in the US. Direct costs of treatment were calculated based on treatment patterns described in publications identified in the literature review. Indirect costs were not included in this analysis. Results: Mastocytosis is a hematopoietic stem cell disorder with pathological mast cell proliferation in tissues. Bone marrow, liver, spleen, gastrointestinal tract, and musculoskeletal systems are most often involved in ASM, and release of various mediators results in symptoms/conditions which can be severe or even debilitating, including anaphylaxis and allergic reactions, osteoporosis, hepatomegaly, splenomegaly, peptic ulcers, ascites, nausea/vomiting, diarrhea, fatigue, and weight loss. Treatment of ASM focuses on symptom reduction with antihistamines, bisphosphonates, glucocorticoids, proton pump inhibitors and mast cell stabilizers. Medications used to control the disease include interferon-alpha, cladribine (2CdA), hydroxyurea, and imatinib or investigational agents in clinical trials. Two studies examining the burden of ASM on patient quality of life or productivity were identified. In one study, (Hermine O et al., PLoS ONE 2008; 3(5): e2266) 82% of systemic mastocytosis (SM) patients stated they suffer from a disability, with 28% reporting it as severe or intolerable. A recently published study (Nowak A et al., JDDG 2011; 9: 525–532) reported 64% of mastocytosis patients commented that the disease moderately to severely restricted their quality of life. No publications were found in the literature search that provided estimates of the annual incidence or prevalence of ASM in the US. The annual prevalence of ASM was calculated using an Orphanet estimate for the global prevalence rate of 0.2 cases per 100,000 individuals multiplied by age- and gender-specific US Census population projections. The annual prevalence of ASM in the US was estimated at 428 patients age ≥20 years in 2010. An annual incidence estimate for the US was calculated by multiplying age- and gender-specific US Census population projections by an assumption of the percentage of SM patients with ASM based on a retrospective cohort study of patients with SM and a published estimate for the incidence rate of SM in the US. Using this method, the annual incidence of ASM was estimated at 77 patients ≥ age 20 in the US in 2010, with an incidence rate of 0.036 cases/100,000 individuals. In a published study of a large cohort of patients with SM, the median age of ASM patients was 65 years vs. 57 years for all SM patients. The median survival for ASM patients was 41 months vs. 63 months for all SM patients. No studies were identified that examined the economic burden of ASM. Direct costs were estimated to be between $5,315 and $8,741 per patient per month. The majority of direct costs were associated with medications; while this is consistent with treatment based on symptom alleviation, it is also due to the fact that the publications used for estimation provided limited information on resource utilization, especially outpatient and ER visits, and as such resource utilization is likely underestimated. Conclusions: These results provide preliminary estimates for the economic burden of ASM in the US. Additional research can assist in further quantifying healthcare resource utilization in ASM, especially ASM-related ER and outpatient visits. Due to the variety of symptoms experienced by ASM patients, the lack of a curative therapy, and shorter survival, it is likely that patients with ASM experience indirect costs (e.g., limitations in functioning or productivity) that may exceed the direct costs of treatment, and further evaluation is warranted. Disclosures: Sotak: Novartis: Research Funding. Marin:Novartis: Research Funding. Coombs:Novartis: Employment. Teitelbaum:Novartis: Research Funding.

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Aleukemic Mast Cell Leukemia (aMCL) - Clinical Characteristics and Outcomes

Blood ◽

10.1182/blood.v128.22.4255.4255 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4255-4255 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Sa Wang ◽

Hagop M. Kantarjian ◽

Nawid Sarwari ◽

Keyur P. Patel ◽

...

Keyword(s):

Overall Survival ◽

Mast Cell ◽

Mast Cells ◽

Research Funding ◽

Median Overall Survival ◽

Systemic Mastocytosis ◽

Cell Transplant ◽

Cell Leukemia ◽

Mast Cell Leukemia

Abstract ABSTRACT Introduction: Systemic mastocytosis (SM) is a complex and rare disease of clonal mast cells. Mast cell leukemia (MCL) is a very rare form of SM seen in <1% patients. We describe here our experience with MCL patients treated at our institution. Methods: We reviewed the medical records of 218 patients with mastocytosis who presented to our institution between 1994 and 2016. The survival of patients was calculated from the date of initial presentation to the date of last follow up. Kaplan-Meier product limit method was used to estimate the median survival. Results: From the 218 patients with mastocytosis, we identified 13 patients with MCL (6.5%). All 13 had aleukemic variant of MCL (aMCL; no presence of mast cells in blood measured by standard CBC technique but with ≥ 20% atypical mast cells in the marrow aspirate). In addition, in 4 of 13 patients, associated hematologic neoplasm (AHN) was present: 2 with myelodysplastic syndrome, 1 with chronic myelomonocytic leukemia and 1 with multiple myeloma. Median age of 13 patients was 62 years (range 24-75 years). Baseline features are summarized in Table-1. During their initial clinical presentation, 85% had constitutional symptoms, 54% had skin rash and other cutaneous symptoms, 31% gastrointestinal symptoms and 23% had joint pains. Imaging studies were performed in 6 patients: 5/6 had enlarged liver and/or spleen, 3 patients had nodal involvement, 2 had sclerotic bony lesions and 1 pt had adrenal involvement. Serum tryptase was >200 ng/ml in all the patients. Testing for c-KITD816V mutation was performed in 9 patients using mutation-specific quantitative (real-time) PCR, of which mutation was undetectable in 6 and detected in 3 patients. The sensitivity of detection was approximately 1 in 1000 mutation-bearing cells. None had FIP1L1-PDGFRA mutations. Treatments given were heterogeneous. Two patients each received imatinib with no response, 2 received dasatinib (one [positive for KITD816V mutation] had significant improvement in hepatosplenomegaly and pruritus but progressed after 1 year of dasatinib therapy), 2 cladribine based therapy with no response, and 2 with stem cell transplant and progression after it. Overall, median follow up was 111 months (1.4-131); 3 patients were alive and 9 died at the time of last follow up. Interestingly, among our 13 aMCL patients, those 4 with AHN appear to have had worse outcome: Figure-1A, shows the median overall survival (OS) of aMCL vs aMCL-AHN (32 vs 25 months; p=0.22). Overall, the median overall survival (OS) of aMCL without AHN was significantly inferior compared to aggressive systemic mastocytosis (ASM) and indolent systemic mastocytosis (ISM) without AHN: 31 months and not reached respectively (Figure-1B; p<0.001). Conclusions: In this analysis, we have shown that aMCL is very rare and these patients have very poor outcome. Based on the recent data from Gotlib et al NEJM 2016, role of midostaurin in the treatment of MCL should be explored. Further studies to characterize the genomic profile of patients with MCL are needed to identify potential therapeutic targets and disease resistance pathways. Table Survival of patients with aleukemic mast cell leukemia (aMCL) with/without AHN (A) and survival comparison of aMCL to other types of systemic mastocytosis, all without AHN (B) Table. Survival of patients with aleukemic mast cell leukemia (aMCL) with/without AHN (A) and survival comparison of aMCL to other types of systemic mastocytosis, all without AHN (B) Figure Figure. Disclosures Daver: Sunesis: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Verstovsek:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; AstraZeneca: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; CTI BioPharma Corp: Research Funding; Lilly Oncology: Research Funding; NS Pharma: Research Funding; Geron: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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Plasma cytokine profiles associated with rhodesiense sleeping sickness and falciparum malaria co-infection in North Eastern Uganda

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-019-0377-7 ◽

2019 ◽

Vol 15 (1) ◽

Author(s):

Julius Nsubuga ◽

Charles Drago Kato ◽

Ann Nanteza ◽

Enock Matovu ◽

Vincent Pius Alibu

Keyword(s):

Transforming Growth Factor ◽

Cytokine Response ◽

Healthy Controls ◽

Plasma Cytokine ◽

Tnf Α ◽

Significant Difference ◽

Cytokine Levels ◽

North Eastern ◽

Ifn Γ ◽

Eastern Uganda

Abstract Background Immunological Human African Trypanosomiasis (HAT) studies often exclude malaria, although both infections overlap in specific endemic areas. During this co-infection, it is not known whether this parasitic interaction induces synergistic or antagonistic cytokine response among humans. This study determined prevalence of Plasmodium falciparum malaria among Trypanosoma brucei rhodesiense HAT and plasma cytokine profile levels associated with HAT and/or malaria infections. Methods Participants were recruited at Lwala hospital in north eastern Uganda: healthy controls (30), malaria (28), HAT (17), HAT and malaria (15) diagnosed by microscopy and PCR was carried out for parasite species identification. Plasma cytokine levels of Interferon-gamma (IFN-γ), Tumour Necrosis Factor-alpha (TNF-α), Interleukin (IL)-6, IL-10 and Transforming Growth Factor-beta (TGF-β) were measured by sandwich Enzyme-Linked Immuno Sorbent Assay and data statistically analysed using Graphpad Prism 6.0. Results The prevalence of P. falciparum malaria among T. rhodesiense HAT cases was high (46.8%). Malaria and/or HAT cases presented significant higher plasma cytokine levels of IFN-γ, TNF-α, IL-6, IL-10 and TGF-β than healthy controls (P < 0.05). Levels of IFN-γ, IL-6 and IL-10 were significantly elevated in HAT over malaria (P < 0.05) but no significant difference in TNF-α and TGF-β between HAT and malaria (P > 0.05). Co-infection expressed significantly higher plasma IFN-γ, IL-6, and IL-10 levels than malaria (P < 0.05) but no significant difference with HAT mono-infection (P > 0.05). The TNF-α level was significantly elevated in co-infection over HAT or malaria mono-infections (P < 0.05) unlike TGF-β level. Significant positive correlations were identified between IFN-γ verses TNF-α and IL-6 verses IL-10 in co-infection (Spearman’s P < 0.05). Conclusions The T. b. rhodesiense significantly induced the cytokine response more than P. falciparum infections. Co-infection led to synergistic stimulation of pro-inflammatory (IFN-γ, TNF-α), and anti-inflammatory (IL-6, and IL-10) cytokine responses relative to malaria mono-infection. Level of TNF-α partially indicates the effect induced by T. b. rhodesiense and P. falciparum mono-infections or a synergistic interaction of co-infections which may have adverse effects on pathogenesis, prognosis and resolution of the infections. Trial registration VCD-IRC/021, 26/08/2011; HS 1089, 16/01/2012

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Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms22062983 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2983

Author(s):

William Shomali ◽

Jason Gotlib

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Organ Damage ◽

Response Criteria ◽

Molecular Response ◽

Tryptase Level ◽

Hematologic Neoplasm ◽

Kit D816v

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

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A correlation between the fluctuations of cytokine concentrations measured in the morning and evening and the circadian blood pressure rhythm in patients with stage II essential hypertension

Bulletin of Russian State Medical University ◽

10.24075/brsmu.2019.011 ◽

2019 ◽

pp. 65-70 ◽

Cited By ~ 1

Author(s):

OA Radaeva ◽

AS Simbirtsev ◽

AV Khovryakov

Keyword(s):

Blood Pressure ◽

Essential Hypertension ◽

Blood Pressure Monitoring ◽

Organ Damage ◽

Time Of Day ◽

Stage Ii ◽

Healthy Controls ◽

Cytokine Levels ◽

Pathophysiological Role

Today, increasing attention is being paid to the role of circadian rhythms in pathology. There are time-of-day-dependent immune markers that provide valuable information about disease progression. The aim of this study was to measure evening and morning concentrations of a few cytokines (interleukins, adhesion molecules, tumor necrosis/growth factors, etc.) in the peripheral blood of patients with stage II essential hypertension and to investigate how they correlate with a nocturnal blood pressure decline. Blood samples were collected from 90 patients with stage II EH at 7:00 a.m. and 8:00 p.m. Cytokine concentrations were measured using immunoassays. Based on 24-h blood pressure monitoring, the patients were distributed into 3 groups: dippers, non-dippers and night-peakers. The morning to evening ratios of cytokine concentrations in patients with EH differed from those in healthy controls due to an increase in the evening concentrations of somnogenic cytokines (IL1β, IL1α) and LIF, sLIFr, and M-CSF whose daily fluctuations patterns remain understudied. On the whole, the fluctuation patterns of the measured cytokines in patients with stage II EH who had had the condition for 10 to 14 years and were receiving no antihypertensive treatment at the time of our study differed from those displayed by healthy controls. A twenty percent rise in the evening concentrations of IL1α, LIF, sLIFr, M-CSF, and erythropoietin contributes significantly to pathological blood pressure rhythms (as demonstrated by the groups of non-dippers and night-peakers) in patients with stage II EH receiving no antihypertensive therapy. Understanding the pathophysiological role of cytokine levels and their fluctuations over a 24-h cycle could inspire new methods for EH prevention and reduce end-organ damage.

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Hypereosinophilia in 357 Consecutive Patients: Disease Spectrum and Clinical and Laboratory Correlates.

Blood ◽

10.1182/blood.v114.22.3903.3903 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3903-3903

Author(s):

Ken-Hong Lim ◽

Ayalew Tefferi ◽

Chin Yang Li ◽

Animesh D. Pardanani

Keyword(s):

T Cell ◽

Research Funding ◽

Clinical Characteristics ◽

Systemic Mastocytosis ◽

Organ Damage ◽

The United States ◽

Parasitic Infections ◽

Myeloid Malignancy ◽

Myeloid Neoplasm ◽

Disease Spectrum

Abstract Abstract 3903 Poster Board III-839 Background A peripheral blood (PB) absolute eosinophil count (AEC) of ≥ 1.5 × 109/L is operationally referred to as “hypereosinophilia”. In general, one can classify hypereosinophilia into 3 major categories: i) secondary, ii) clonal, and iii) idiopathic. The 2008 WHO proposal provides a modern-era framework for the classification of clonal eosinophilia and subcategories include (i) myeloid/lymphoid neoplasms associated with eosinophilia and PDGFRA-, PDGFRB-, or FGFR1-rearrangement; (ii) clonal eosinophilia associated with an otherwise WHO-defined myeloid malignancy such as systemic mastocytosis (MN-eo), and (iii) chronic eosinophilic leukemia, otherwise not specified (CEL-NOS). Idiopathic hypereosinophilia (IH) with organ damage and without clonal/abnormal lymphocytes is referred to as hypereosinophilic syndrome (HES). In the current study, we define the spectrum of disease phenotypes and survival in 357 consecutive patients with hypereosinophilia seen at a single institution. Methods Mayo Clinic patient records from January 1994 to October 2008 were reviewed, and those with persistent eosinophilia ≥1.5 × 109/L identified. Clinical data and bone marrow (BM) histology were reviewed, and the eosinophilic disorder classified as above. The aims of the current study were to: (i) study the spectrum of eosinophilic disorders within the context of the WHO proposal; (ii) describe the clinical, laboratory, and molecular/cytogenetic characteristics of patients with primary eosinophilia (i.e. clonal and idiopathic); and (iii) assess the prognostic relevance of the WHO proposal from the standpoint of life expectancy and risk of leukemic transformation. Results (i) Disease spectrum and clinical characteristics: A total of 357 cases (median age=52 years) were identified: (i) secondary eosinophilia 165 (46%; male ∼52%) (autoimmune 33%, non-myeloid malignancy 19%, drugs 12%, allergies 10%, parasitosis 2%, others 24%); (ii) PDGFRA- or PDGFRB-rearranged myeloid neoplasm 17 (5%; male 100%); (iii) CEL-NOS 6 (2%; male 67%); (iv) MN/eo 36 (10%; male 69%) (systemic mastocytosis 50%, chronic myeloproliferative neoplasm 33%, AML 6%, others 11%); (v) IH 115 (32%; male 58%); and (vi) eosinophilia associated with clonal/abnormal lymphocytes 14 (4%; male 57%). Of the 115 patients with IH, 72 (63%) had evidence of end-organ damage, and could be classified as having HES: 36 patients had 1 organ involved, 21 had 2, and 15 had 3-4. In HES patients, the major organs involved were: lung 23%, skin/mucosa 22%, cardiac 14%, nervous system 10%, and thrombosis 9%. (ii) Molecular and cytogenetic abnormalities: Complete karyotype information was available for 144 (77%) patients; 21 (15%) patients had an abnormal karyotype; MN/eo 12 (35%), PDGFRA- or PDGFRB-rearranged myeloid neoplasm 4 (31%), CEL-NOS 5 (83%), IH and eosinophilia associated with clonal/abnormal lymphocytes 0 (p<0.01). Of the 126 (67%) patients screened for FIP1L1-PDGFRA, 16 (13%) tested positive. Two patients (1%) harbored t(5;12). Of the 108 (57%) patients screened for presence of an occult T-cell clone (PCR for TCR gene rearrangement), 14 (13%) tested positive. (iii) Survival and risk of disease transformation: At a median follow of 21 months (range <1-174), 56 (30%) deaths were recorded; MN/eo 23 (64%), IH 25 (22%), PDGFRA- or PDGFRB-rearranged myeloid neoplasm 3 (18%), CEL-NOS 3 (50%), and T-cell/eo 2 (14%). The combined median survival was 95 months: MN/eo 34 months, CEL-NOS 13 months, IH 151 months, PDGFRA- or PDGFRB-rearranged myeloid neoplasm and eosinophilia associated with an abnormal lymphocyte clone (not reached) (p<0.01; Figure). Transformation to acute leukemia was seen in 4 patients (2 with PDGFRA- or PDGFRB-rearranged myeloid neoplasm, and 1 each with CEL-NOS and IH) (p<0.01). Conclusions In a major tertiary center in the United States, the two major causes of hypereosinophilia were secondary (46%) and idiopathic (32%). Regarding the former, autoimmune diseases and parasitic infections were the most and least frequent causes, respectively. Cases with clonal eosinophilia were predominantly male while the sex ratio was more balanced in the other subcategories. Among primary hypereosinophilia, survival was the worst in clonal eosinophilia not associated with the imatinib-sensitive PDGFR mutations. Additional data regarding clinical characteristics, laboratory findings, and treatment outcome of idiopathic hypereosinophilia patients will be presented at the meeting. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding.

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