DR NOA LAVI 2019

Approach to Eosinophilic syndrome

Approach to Eosinophilic syndrome▪Definitions, classification

▪ Clinical presentation

▪Diagnosis

▪Prognosis

▪ Treatment

Definitions and Classifications▪ Severity of eosinophilia is arbitrarily divided into mild (AEC from ULN to 1.5 × 109/L), moderate (AEC 1.5-5 × 109/L) and severe (AEC >5 × 109/L)

▪ Hypereosinophilia (HE): persistent eosinophilia of >1.5 × 109/L

▪ HEFA- hereditary (familial) variant

▪ HEUS-HE of undetermined significance (“idiopathic HE”)

▪ HEN- primary (clonal/neoplastic) HE produced by clonal/neoplastic eosinophils

▪ HER- secondary (reactive) HE, including the lymphocyte variant

▪ HES- Any HE (not just idiopathic) associated with organ damage

The Shrinking Pool of idiopathic HES

Revised WHO classification of myeloid neoplasms

Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2❖ PDGFRA- Presence of a FIP1L1-PDGFRA fusion gene or a variant fusion gene with rearrangement of PDGFRA. If molecular analysis is not available, Dx should be suspected if there is a Ph(-) MPN with hematologic features of CEL associated with splenomegaly, a marked elevated vitamin B12, elevated serum tryptase, and increased BM mast cells

❖PDGFRB- Presence of t(5;12)(q31~q33;p12) or a variant translocation or demonstration of an ETV6-PDGFRB fusion gene or rearrangement of PDGFRB. Because t(5;l2)(q31~q33;p12) does not always lead to an ETV6-PDGFRB fusion gene, molecular confirmation is highly desirable. If molecular analysis is not available, Dx should be suspected if there is a Ph (-) MPN associated with eosinophilia and with a translocation with a 5q31~33 breakpoint

❖FGFR1- Presence of t(8;13)(p11;q12) or a variant translocation leading to FGFR1 rearrangement

❖ PCM1-JAK2- Presence of t(8;9)(p22;p24.1) or a variant translocation leading to JAK2 rearrangement (alternative partner include ETV6-JAK2 [t(9;12)(p24.1;p13.2)] or BCR-JAK2 [t(9;22)(p24.1;q11.2)]

PDGFRA-rearranged Myeloid Neoplasms•Overwhelmingly male

•Not visible with standard cytogenetics –Detectable by FISH or RT-PCR

•Elevated serum tryptase

•The ‘myeloproliferative variant of hypereosinophilia’

–BM fibrosis and increased mast cells , Splenomegaly, Anemia and/or thrombocytopenia

•Increased incidence of potentially lethal cardiac involvement in absence of therapy

CES-NOS❖ Eosinophilia (eosinophil count >1.5 × 109/L)

❖Not meeting WHO criteria for PH(+) CML, PV, ET, PMF, CNL, CMML, or atypical CML

❖No rearrangement of PDGFRA, PDGFRB, or FGFR1; no PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion gene

❖ Blast cell count in peripheral blood and BM < 20%, and inv(16) and other diagnostic features of AML are absent

❖ A clonal cytogenetic or molecular genetic abnormality, or blast cells are ≥2% in peripheral blood or > 5% in the BM

It is not always clear whether specific mutation(s) identified on NGS panels are pathogenetically related to the eosinophilic neoplasm (eg, CHIP mutation, or variant of unknown significance), and should be interpreted with caution

Clinical Presentationo Most common presenting signs and symptoms: weakness and fatigue (26%), cough (24%), dyspnea (16%), myalgias or angioedema (14%), rash or fever (12%), rhinitis (10%)

o Anemia 53% of patients, thrombocytopenia more common than thrombocytosis (31% vs 16%)

o During follow-up of patients with HE, dermatologic involvement most common (69%), followed by pulmonary (44%) and gastrointestinal (38%) manifestations. Cardiac disease was eventually identified in 20% of patients (only 6% at the time of initial presentation)

o Endocardial damage with resulting platelet thrombus can lead to mural thrombi and increased embolic risk. In the later fibrotic stage, fibrous thickening of the endocardial lining can evolve to a restrictive cardiomyopathy. Valvular insufficiency results from mural endocardial thrombosis, and fibrosis involving leaflets of the mitral or tricuspid valves

Neurologic diseaseCerebral thromboemboli can arise from intracardiac thrombi

Encephalopathy can present with behavioral changes, confusion, ataxia, and memory loss. More likely with markedly elevated blood leukocyte and eosinophils, may derive from microvascular occlusion

Peripheral neuropathy The neuropathy may be symmetric/asymmetric, involve sensory +/-motor nerves, may produce mononeuritis multiplex or radiculopathy

Thrombotic complicationsPatients have been reported to develop femoral artery occlusion, intracranial sinus thrombosis, digital gangrene in the setting of progressive Raynaud's phenomenon

While eosinophils may impact coagulation pathways at different levels, the precise mechanisms leading to hypercoagulability remain elusive

Thrombotic and thromboembolic events are a major cause of morbidity, high degree of suspicion must be maintained

Available series suggest that ¼ of patients with HES develop thromboembolic complications

Dx Step 1: Exclude secondary (reactive) causes of eosinophilia

❖Ova and parasite testing, stool culture, and antibody testing for specific parasites (eg, strongyloides)❖Elevated IgE-mostly in reactive HE❖ANA, ANCA❖Bronchoscopy, serologic tests (eg, aspergillus IgE to evaluate for ABPA)

If secondary causes of eosinophilia are excluded, work-up should proceed to the evaluation of a primary bone marrow disorder

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אירועים של נימול ביד בשבועיים אחרונים3טרם אשפוז

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סרולוגיה לסטרונגילואידיס וסכיסטוזומה שלילי, צואה לפרזיטים שלילי

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מוח תקיןMRI-אירועים שפחות מפוקס

Exclude secondary

causes

Dx step 2: Evaluate for primary (clonal)eosinophilia

Blood smear: circulating blasts, dysplastic cells, monocytosis

Laboratory evaluation of primary eosinophilia should begin with screening of peripheral blood for FIP1L1-PDGFRA gene fusion

(KIT D816V, NGS Panel, BCR-ABL, JAK2)

HES/CEL and NGS❖With availability of NGS panels, identification of additional mutations in cases of idiopathic hypereosinophilia is expected to be more common, relegating patients to the category of CEL-NOS

❖ Among 426 pts in the German Registry with HEUS, KIT D816V and JAK2 V617F mutations were identified in 3% and 4% of pts, respectively

❖Another study found myeloid mutations in 14/51 patients with a diagnosis of HES

❖Most commonly mutated genes were: ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), NOTCH1 (14%)

❖Pts with HES with positive sequencing exhibited a prognosis inferior to HES pts without mutation, but similar to pts with CEL-NOS

❖ Recently, an activating STAT5B N642H variant, was identified in 27/1715 (1.6%) cases referred for eosinophilia. Pts with additional mutated genes (other than SF3B1) had an inferior OS compared to those with STAT5B mutations alone, or if the additional mutated genes included SF3B1 (median survival of 14 vs 65 months, respectively)

Lymphocyte-Variant Hypereosinophilia ▪Clonal expansion of abnormal T-lymphocytes, secrete high levels of eosinophilopoietic cytokines, e.g IL-5

▪The immunophenotype of these lymphocytes (blood or marrow) include:

▪double-negative, immature T-cells (eg, CD3+CD4−CD8−) or absence of CD3 (eg, CD3−CD4+)

▪ Additional immunophenotypic abnormalities include elevated CD5 expression on CD3−CD4+ cells, loss of surface CD7 and/or expression of CD27

▪Isolated T-cell clonality by PCR without T-cell immunophenotypic abnormalities, is not felt to be sufficient to make a dx of this eosinophilia variant

▪A recent study demonstrating that a high proportion of idiopathic HES patients exhibit a clonal TCR gene rearrangement by PCR (43%), unclear whether such clonal T-cell populations are always relevant to the disease process, and clonal TCR rearrangements are highly prevalent in pts with various HES subtypes, including pts with PDGFRA rearrangement

Lymphocyte-Variant Hypereosinophilia ▪Primarily skin symptoms and benign course, although other clinical manifestations including cardiac involvement, can be present

▪The abnormal T cells produce other cytokines leads to increased IgE synthesis and polyclonal hypergammaglobulinemia

▪Increased risk of development of T-cell lymphoma

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FIP1L1-PDGFRAשלילי בדם ב-PCR

BCR-ABLשלילי

TCRפוליקלונלי

BMA-חשוד ל. ריבוי ניכר של מגהקריוציטים, ריבוי אזונופילים ופרקורסורים של אזונופילים, לשד היפרצלולרי-MPN

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BMB- שורה לבנה היפרפלסטית . רובם דיספלסטים, ריבוי ניכר של מגהקריוציטים. אין ריבוי סיבי רטיקולין. 60%צלולריותחשד למחלה . CD34 C117ריבוי קל מאוד של תאים צעירים שנצבעו . שורה אדומה בכמות טובה. עם ריבוי אזונופילים

מילופרולפרטיבית כרונית

11טריזומיה של כרומוזום -קריוטיפ

NGS-מוטציה ידועה ב-SRSF2

FISHל—PDGRAPDGFRBשלילי ממח עצם

KIT D816Vשלילי

Evaluate for primary (clonal)

eosinophilia

Prognosis❖ In a recent Mayo Clinic report of 98 patients with HES and idiopathic hypereosinophilia, a multivariate analysis revealed: age >60 years, hemoglobin <10 g/dL, cardiac involvement, and hepatosplenomegaly were associated with inferior OS

❖11% harbored a pathogenetic mutation in one of the following genes: TET2, ASXL1, KIT, IDH2, JAK2, SF3B1, and TP53, but the presence of one of the mutations was only significant in a univariate analysis of survival

❖The prognosis of CEL-NOS is poor. In a cohort of 10 patients, the median survival was 22.2 months, and 5 of the 10 pts developed acute transformation after median of 20 months from diagnosis

❖ Lymphocyte-variant of hypereosinophilia, has an indolent disease course. However, pts may infrequently develop or present concomitantly with either T-cell lymphoma or Sézary syndrome

❖Accumulation of cytogenetic changes in T-cells, and proliferation of lymphocytes with the CD3−CD4+ phenotype have been observed with progression to lymphoma

Treatment of PDGFRA positive HESFirst-line therapy imatinib, treatment should be initiated promptly, to prevent end organ damage

Patients with potential cardiac disease (elevated troponin and/or abnormalities on echo), concomitant glucocorticoids during the first 7-10 days when imatinib is initiated to prevent acute necrotizing myocarditis

Clinical, hematological, and molecular remission in the majority of patients. Symptoms resolve and eosinophil counts normalize, generally within 1-2 weeks

Cardiac symptoms and fixed neurological deficits may not improve

Imatinib doses required to induce molecular remission are lower than CML, thus, dose-related side effects are uncommon

Treatment of PDGFRA positive HESThe recommended starting dose for pts with the FIP1L1-PDGFRA rearrangement is 100 mg daily

Some pts may require higher maintenance doses in the range of 300-400 mg daily

Maintenance dose of 100-200 mg/wk may be sufficient to sustain a molecular remission in some pts

Imatinib can effectively suppress, but not eliminate the FIP1L1-PDGFRA clone in most patients, although some may experience prolonged molecular remissions after stoppage of imatinib, ongoing treatment is generally recommended

Very few cases of acquired imatinib resistance have been reported

Most involved the T674I mutation, and have occurred during the blast phase of the disease

The T674I mutation confers resistance to tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

For patients with myeloid neoplasms with eosinophilia and rearranged PDGFRB, the recommended dose is 400 mg daily, lowered to 100 mg during maintenance

FGFR1, JAK2 AND FLT3-REARRANGEDNEOPLASMSThe natural history of patients with a myeloid/ lymphoid neoplasm with rearranged FGFR1 follows an aggressive course usually terminating in AML or T-ALL in 1-2 years

Therefore, intensive chemotherapy followed by early allogeneic transplantation, has been recommended

FGFR1 inhibition (pemigatinib) is currently being evaluated in the clinical trial setting with encouraging responses

The JAK2 and FLT3 tyrosine kinase inhibitors can be considered on an-off label or clinical trial

basis, as a bridge to HSCT in patients with JAK2 and FLT3 tyrosine kinase fusions

Treatment of HES and CEL-NOS: Corticosteroids, Hydroxyurea, IFN-AlfaTherapy is indicated for symptomatic pts or those with evidence of end organ damage

For pts with strictly defined HES (eg, exclusion of all other possible causes of HE), corticosteroids (eg, prednisone 1 mg/kg for 1-2 weeks) are the mainstay of therapy, and are effective in producing rapid reductions in the eosinophil count

Empiric treatment for Strongyloides (eg, with ivermectin) can be considered in the appropriate clinical context while serum antibody testing is pending, to prevent steroid-induced hyperinfection syndrome and disseminated disease

With symptom control and reduction of the eosinophil < 1.5 × 109/L, corticosteroids can usually be tapered

Glucocorticoids-highly effective, 85% PR/CR at one month

Recrudescence of symptoms, signs of organ damage, and/or significant increase of the eosinophil count with a prednisone dose >10 mg daily is an indication for the addition of other agents

Hydrea& IFN-αHydroxyurea is an effective first-line agent for HES which may be used in conjunction with corticosteroids or in steroid non-responders

A typical starting dose is 500-1000 mg daily

IFN-α can produce hematologic and cytogenetic remissions in HES and CEL pts refractory to other therapies including prednisone and/ or hydroxyurea, or can be used in conjunction with corticosteroids as a steroid-sparing agent for individuals requiring higher doses of prednisone

Initiation of therapy at 1 million units by sc injection 3 times weekly (tiw), and gradual escalation of the dose to 3-4 million units tiw or higher may be required to control hypereosinophilia in some pts

ChemotherapyHematologic benefit has been observed with second-line and third-line agents, including vincristine, cyclophosphamide, and etoposide.

Responses to 2-CDA alone or in combination with cytarabine, and cyclosporine-A have also been reported

Recently, dexpramipexole (an oral synthetic aminobenzothiazole) was incidentally found to decrease absolute eosinophil counts by an unknown mechanism in a phase 3 trial of ALS

A small proof of concept study of 10 steroid-responsive HES patients (none with myeloproliferative HES), reported that 4 out of 10 patients were able to achieve ≥50% reduction in the minimum effective oral glucocorticoid dose, to maintain an AEC <1 × 109/L with control of clinical symptoms

ImatinibIn selected cases, patients with CEL, NOS or HES may benefit from imatinib, usually administered at higher doses (> 400 mg daily)

However, hematologic responses in this group are more often partial, short lived, and may reflect drug-related myelosuppression

Rare complete responses may represent diagnostically occult PDGFRA or PDGFRB mutations, or other unknown pathogenic targets

If a response is not observed within 2-4 weeks, imatinib should be discontinued

Treatment of Lymphocyte-VariantHypereosinophiliaPts should initially be treated with corticosteroids

Patients who are refractory to therapy or exhibit relapse may be considered for treatment with IFN-α or steroid-sparing immunosuppressive agents

Hydroxyurea and imatinib are less likely to demonstrate efficacy in this lymphocyte-variant of hypereosinophilia

Anti-IL5

Mepolizumab- In HES patients, regression of constitutional symptoms, eosinophilic dermatologic lesions, and improvements of FEV1 measurements in individuals with pulmonary disease have been observed with Tachyphylaxis has been observed with repeated doses without development of neutralizing antibodies

Mepolizumab is not currently approved by the FDA for HES (approved for severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis)

Reslizumab is a humanized anti-IL5 IgG4 mAb approved by the FDA for severe eosinophilic asthma. It has not yet been evaluate extensively in HES

Benralizumab- Benralizumab has been evaluated in 20 patients with PDGFRA-negative HES in a small randomized, double blind, placebo-controlled, phase 2 trial. 9/10 pts in the benralizumab arm met the primary endpoint of at least 50% reduction in the AEC at

12 wks (P = .02)

Gotlib et al AJH 2019

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ממתינים לרמת טריפטאז

M-HES is defined for the purposes of this algorithm as:

HES with a genetic abnormalityknown to cause clonal eosinophilia

or idiopathic HES with ≥ 4 of the following features: 1. dysplastic eosinophils2. serum B12 > 737.8 pM (1000 pg/mL)3. serum tryptase >12 ng/mL4. anemia and/or thrombocytopenia5. Splenomegaly6. bone marrow cellularity>80%7. Myelofibrosis8. spindle-shaped mast cells>25%

orStrong clinical suspicion of a myeloproliferative disorder

?CEL-NOS ?Idiopathic HESעם 68י בן .ז

Planning for disease progressionEarly HLA typing for possible allogeneic HSCT should be considered for patients with any of the following:

●FIP1L1/PDGFRA-associated HES

●Cytogenetic abnormalities

●Potentially life-threatening end-organ involvement (especially cardiac or CNS involvement)

●Features of myeloproliferative disease

In HES patients who fail pharmacologic management, allogeneic hematopoietic cell transplant offers a chance of long-term remission

Problem specific interventionsCardiovascular disease — Valve replacement/repair, endomyocardectomy, or thrombectomy to patients who develop valvular compromise or endomyocardial thrombosis or fibrosis

Bioprosthetic valve replacement is indicated - thrombosis of mechanical valves has occurred despite anticoagulation

Anticoagulation — warfarin and/or antiplatelet agents is often instituted once an embolic event has occurred

Warfarin is usually initiated for a thrombus in the heart, venous thrombus in an intracranial sinus.

Thrombosis formation is a consequence of local and not systemic proclivity to thrombosis, may not be suppressed by systemic anticoagulation

MonitoringIn a stable patient on chronic low dose glucocorticoids: clinical assessment every 6 - 12 months

Patients with continued symptoms and eosinophilia despite aggressive therapy may need to be evaluated weekly

Monthly eosinophil counts are recommended with additional testing depending on the therapeutic agent being used and the end organs involved

Serum troponin assays, liver enzymes, echocardiography, and pulmonary function tests should be performed every 6-12 months

Monitoring-contBecause of increased risk for lymphoma, patients with L-HES should be monitored:

every 3-4 months for development of lymphocytosis

every 6 months with flow cytometry to assess an increase in aberrant T cells

Karyotyping yearly

Enlarged LNs or changes in skin lesions - biopsy

Patients with FIP1L1/PDGFRA on imatinib in molecular remission should be monitored:

every 3 months: CBC with differential, liver profile, troponin (drug-associated

cardiomyopathy)

every 3-4 months, FIP1L1/PDFGRA should repeated, early marker of therapeutic failure

References❑ Gotlib et al. World Health Organization-defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management. Am J Hematol. 2019;94:1149–1167

❑Klion How I treat hypereosinophilic syndromes. Blood 2015

Dx studies:נספח א

לאן לשלוח בארץ בדיקות מיוחדות:נספח ב❖PCRל-PDGFRA–83896קוד -מעבדה להמטולוגיה מולקולרית תל השומר

❖FISHל-PDGFRA PDGFB (בני ציון, רמבם-בצפון)יש במספר מעבדות לציטוגנטיקה בארץ

-02-טל= משרד הבריאות ירושלים, המרכז לפרזיטולוגיה-סרולוגיה לסטרונגילואידיס וסכיסטוזומה❖6551884

. שח365-עלות, 09-7472198-פזית/אירית, ח מאיר"בי, מעבדה לאימונלוגיה קלינית-טריפטאז בדם❖סמק בקירור3–מבחנה צהובה . 09-7471957-תשלום בקופה