A multimodality work-up of patients with Hypereosinophilia.

The work-up of patients with hypereosinophilia (HE) is complex. Following the recently revised World Health Organization criteria, we retrospectively reviewed 125 patients who were referred to us to exclude a neoplastic cause of HE (2003-2016). The clinical laboratory work-up confirmed secondary HE in 25 (20%) patients; myeloid/lymphoid neoplasms with rearrangements of PDGFRA (n = 9) or PDGFRB (n = 2) (9%); HE associated with a well-defined myeloid neoplasm in 8 (6%); and abnormal bone marrow and/or molecular genetic abnormalities consistent with chronic eosinophilic leukemia (CEL), not otherwise specified (NOS) in 21 (17%) patients. For the remaining 60 (48%) patients, a specific diagnosis was not identified, and 56 patients had HE related findings consistent with idiopathic hypereosinophilic syndrome (HES), while 4 patients who were asymptomatic. With a median follow up of 35.3 months (range, <1-104), patients with CEL, not otherwise specified (NOS) had a median OS of 26.1 months, significantly inferior to patients with idiopathic HES (not reached, P < .01). Thus, our experience in a single tertiary cancer center shows that the work-up of HE following WHO recommendations requires a multimodality-based approach; and a correct diagnosis determines risk stratification and proper patient management. However, the causes of HE remain unknown in approximately half of referred patients, indicating the need for further studies.

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified.

The distinction between chronic eosinophilic leukemia, not otherwise specified and idiopathic hypereosinophilic syndrome largely relies on clonality assessment. Prior to the advent of next-generation sequencing, clonality was usually determined by cytogenetic analysis. We applied targeted next-generation sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of idiopathic hypereosinophilic syndrome patients (n=51), and assessed the significance of mutations in conjunction with clinicopathological features. The findings were further compared with those of 17 chronic eosinophilic leukemia, not otherwise specified patients defined by their abnormal cytogenetics and/or increased blasts. Mutations were detected in 14/51 idiopathic hypereosinophilic syndrome patients (idiopathic hypereosinophilic syndrome/next-generation sequencing-positive) (28%), involving single gene in 7 and ≥2 in 7 patients. The more frequently mutated genes included ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%). Idiopathic hypereosinophilic syndrome/next-generation sequencing-positive patients showed a number of clinical features and bone marrow findings resembling chronic eosinophilic leukemia, not otherwise specified. Chronic eosinophilic leukemia, not otherwise specified patients showed a disease-specific survival of 14.4 months, markedly inferior to idiopathic hypereosinophilic syndrome/next-generation sequencing-negative (P<0.001), but not significantly different from idiopathic hypereosinophilic syndrome/next-generation sequencing-positive (P=0.117). These data suggest that targeted next-generation sequencing helps to establish clonality in a subset of patients with hypereosinophilia that would otherwise be classified as idiopathic hypereosinophilic syndrome. In conjunction with other diagnostic features, mutation data can be used to establish a diagnosis of chronic eosinophilic leukemia, not otherwise specified in patients presenting with hypereosinophilia.

KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance.

Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 µg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of ≥2 × 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.

Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation.

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare disorder with hypereosinophilia and an increased number of blood or marrow blast (<20%) or an evidence of eosinophil clonality.We evaluated the clinical outcome of 10 patients with CEL-NOS. Seven males and three females at a median age of 62 years (range, 23­73) were included. The median leukocyte count at diagnosis was 33.4 3109/l (range, 9.3­175.0) with a median eosinophil count of 15.6 3 109/l (range, 1.5­136.0). Median hemoglobin and platelets were 11.0 g/dl (range, 8.3­13.3) and 158 3 109/l (range, 31.0­891.0), respectively. Clinical manifestations included splenomegaly (n 5 7), hepatomegaly (n 56), cardiac failure (n 5 2), and lung infiltrations (n 5 1). Median survival from diagnosis to death for entire cohort was 22.2 months (range,2.2­186.2). Five of the 10 studied patients developed acute transformation(AT) after median of 20 months from diagnosis (range, 1.6­41.9).None of patients with AT is alive at the time of last follow-up. Median time from AT to death was 2 months (range, 1.0­6.1). Among five patients who did not develop AT, three died in active disease. Two patients are alive in complete remission; first underwent allogeneic stem-cell transplantation preceding by intensive induction chemotherapy;the second remains on imatinib with hydroxyurea. Except the latter patient, imatinib was ineffective in our study population. CEL-NOS is a rare and aggressive disease with high rate of AT and resistance to conventional treatment.

Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies.

PURPOSE: Hypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors. METHODS: To understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndrome n = 18, chronic eosinophilic leukemia not otherwise specified n = 9, lymphocyte-variant hypereosinophilia n = 2, myeloproliferative neoplasm with eosinophilia n = 2, eosinophilic granulomatosis with polyangiitis n = 11, reactive eosinophilia n = 3). RESULTS: Contrary to published literature, we found no difference in the levels of the lncRNA Morrbid and its target BIM. Yet, we identified a near complete loss of expression of pro-apoptotic PUMA as well as a reduction in anti-apoptotic BCL-2. Accordingly, BCL-2 inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast, MCL1 inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful. CONCLUSION: Our study shows that MCL1 inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

Association of Thrombosis With Hypereosinophilic Syndrome in Patients With Genetic Alterations.

Importance: Hypereosinophilic syndromes (HESs) are a rare group of disorders that result in overproduction of eosinophils, leading to tissue damage. Thrombotic complications in HES and associated risk factors in this patient population have not been extensively studied. Objective: To investigate the rates of and risk factors associated with thrombotic events in patients with HES, including markers of clonal hematopoiesis as evidenced by molecular aberrations on next-generation sequencing. Design, Setting, and Participants: This retrospective cohort study evaluated patients seen at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, from January 1, 2015, to January 1, 2020. Patients who had hypereosinophilia with an absolute eosinophil count of 1500 cells/µL or greater on 2 separate occasions at least 1 month apart and who underwent genetic or molecular testing as part of their work-up were included. Patients with secondary eosinophilia were excluded. Main Outcomes and Measures: Symptomatic and asymptomatic arterial and venous thrombotic events after the diagnosis of HES and all-cause death. Results: A total of 71 patients (median age, 58 years [interquartile range (IQR), 43-67 years]; 36 women [51%]; 57 White patients [80%]) were included. Patients had a median follow-up time of 29 months (IQR, 19-49 months). Seventeen patients (24%) had 1 or more thrombotic events, including 11 venous thromboembolic events and 11 arterial thrombotic events (8 patients had ≥1 event and 3 patients had recurrent events). Patients with 1 or more thrombotic events had a higher median Eastern Cooperative Oncology Group performance status (median, 1 [IQR, 1-2] vs 0 [IQR, 0-1]; P = .002), had more frequent cardiac involvement (7 of 17 events [41%] vs 6 of 54 events [11%]; P = .01), more frequently received treatment (17 of 17 events [100%] vs 40 of 54 events [74%]; P = .02), and had more molecular aberrations on next-generation sequencing (12 of 17 [71%] vs 12 of 54 [26%]; P = .003) vs patients without thrombosis. After multivariable analysis, the presence of molecular aberration was associated with increased odds of thrombosis (adjusted odds ratio, 5.4; 95% CI, 1.1-27.7). Death occurred more frequently in patients with thrombotic events compared with those without (6 of 17 [35%] vs 2 of 54 [4%]; P = .002) and in patients with molecular aberrations compared with those without (6 of 24 [25%] vs 1 of 40 [3%]; P = .009), although only thrombotic events were significantly associated with increased odds of death after multivariable analysis. Conclusions and Relevance: In this cohort study, thrombosis was common in patients with HES and was significantly associated with increased risk of death.

Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in China.

BACKGROUND: The FIP1L1/PDGFRA (F/P) fusion gene is the most common clonal genetic abnormality of chronic eosinophilic leukemia (CEL). Tyrosine kinase inhibitors (TKI), such as imatinib, have been demonstrated to be effective therapies for F/P mutated disease. The aim of this study was to analyze the treatment response and long term prognosis in patients with F/P mutated CEL. METHODS: The clinical features and treatment responses of 33 consecutive patients with F/P mutated CEL between August 2006 and October 2014 were analyzed. The 33 cases received imatinib therapy at an initial dose of 100 mg/day (30 patients) or 200 mg/day (3 patients); the maintenance dose depended on the response condition and patient willingness. Through the follow up, the molecular responses were regularly monitored. RESULTS: With a median follow up of 64 months, 94% of the 33 patients with F/P mutated CEL achieved a complete hematologic remission (CHR), and 97% achieved a complete molecular remission (CMR) after a median of 3 (1.5-12) months. Twenty-four cases received maintenance therapy, with a median CMR duration of 43 (5-88) months. Imatinib therapy was discontinued in 8 cases, including 4 cases who experienced relapse, and 4 patients who maintained CHR or CMR after discontinuing therapy with a median time of 47 (2-74) months. One case exhibited primary resistance with a PDGFRA T674I mutation. CONCLUSIONS: F/P mutated CEL has an excellent long-term prognosis following imatinib therapy. A 100 mg daily dose of imatinib is sufficient to induce remission, and a single 100 mg weekly dose maintains a durable remission. A subgroup of patients may maintain a durable remission after discontinuing therapy with a CMR.

Endomyocardial disease and eosinophilia.

The authors discuss the hypereosinophilic syndrome:incidence, terminology, cytotoxicity, clinical presentation and diagnosis, prognosis, and treatment, and they provide a literature review.

Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature.

BACKGROUND: Information in the literature regarding causes of mortality in patients with hypereosinophilic syndrome (HES) is limited. METHODS: This was a retrospective review of the morbidities and causes of death in HES patients at Mayo Clinic. RESULTS: Overall, out of the 247 diagnosed HES patients, 23 died during the 19 years that this review encompassed. The cause of death was identified in 15 patients (65%): cardiac dysfunction in 5 (33%), infection in 3 (20%), unrelated malignancy in 3 (20%), thromboembolic phenomena in 2 (13%), and vascular disease in 2 (13%). CONCLUSION: Targeted monitoring of the at-risk end organs, combined with early treatment, may have the ability to improve survival and reduce morbidity in HES patients.

Effect of the tyrosine kinase inhibitor nilotinib in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia: analysis of the phase 2, open-label, single-arm A2101 study.

PURPOSE: Hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are characterized by sustained overproduction of eosinophils and organ dysfunction. CEL involves the presence of clonal genetic markers, such as a fusion of FIP1-like 1 protein and platelet-derived growth factor receptor α (FIP1L1-PDGFRα, or F/P) or PDGFRα-activating mutations. METHODS: Sixteen patients with HES/CEL were enrolled in the phase 2 nilotinib registration trial (NCT00109707) and treated with nilotinib 400 mg twice daily. The median duration of treatment was 95 days (range 3-1,079). RESULTS: Twelve patients had HES: 1 achieved a complete hematologic response (CHR), 3 achieved stable disease, 3 had progressive disease, and 5 were not evaluable for response. Four patients had CEL: 2 with the F/P fusion and 2 with PDGFRα-activating mutations. Both patients with an F/P fusion achieved a CHR; 1 also achieved a complete molecular response (CMR). Of the 2 patients with PDGFRα-activating mutations, 1 had stable disease and the other achieved CMR. At 24 months, overall survival in the HES group was 75.0 % (95 % CI 50.5-100.0) and no patients in the CEL group died. Median survival was not yet reached after a median follow-up of 32 months. The most common grade 3/4 hematologic laboratory abnormalities were lymphocytopenia (31.3 %) and neutropenia (25.0 %). The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %). CONCLUSIONS: Nilotinib 400 mg twice daily was effective in some patients with HES/CEL regardless of F/P mutation status, and the safety profile was consistent with other nilotinib studies.

Cardiac manifestation of the hypereosinophilic syndrome: new insights.

Cardiac manifestation is the major cause of morbidity in patients with hypereosinophilic syndrome (HES). Clinical features range from heart failure to arterial embolism, which are caused by thickening of the endocardium and mural left ventricular thrombosis. Modern magnetic resonance imaging and echocardiography are able to detect fibrosis, eosinophilic infiltrate and thrombi to stage the fibrotic evolution of the disease. Treatment of HES involves standard medication for heart failure, anticoagulant therapy, immunosuppressive therapy and potentially surgical resection. The outcome of HES depends on both the progression of endocardial fibrosis and associated complications and the 5-year mortality is estimated at 30%.