SPOEDTHERAPIE

http://emedicine.medscape.com/article/202030-treatment

all patients require periodic monitoring for
- organ involvement: not correlated with the degree of blood eosinophilia and may develop insidiously
- vigilance for thrombotic complications
- geen profylactische antistolling
– 1x/3 mnden 1e 1-2 jaar: klachten en lab: algemeen + tropo
– new symptoms: ECG > echo > MRI, CT-thorax/LF
- echocardiography, and pulmonary function tests should be performed every 6 to 12 months to monitor for occult organ involvement?

chronic low-dose glucocorticoids: every 6 to 12 months may be adequate
continued symptoms and eosinophilia despite aggressive therapy: evaluated weekly
on imatinib:
- three months: algemeen lab/tropo once in stable clinical, hematologic, and molecular remission; cave drug-associated cardiomyopathy
- F/P PCR or FISH every three to four months, as this is an early marker of therapeutic failure
L-HES: evaluated every three to six months 
- clinical examination for lymphadenopathy, algemeen lab, IFT
- IFT: toename aberrant T cells on flow cytometry (eg, CD3-CD4+ cells): increased risk for progression, repeat bone marrow biopsy, including a karyotype analysis
- enlarged lymph nodes and changing/suspicious skin lesions biopsied

indicaties
– AEC >100 x 109/L
– leukostasis (ie, pulmonary or neurologic dysfunction in the setting of a white blood cell count >50 x 109/L [>50,000 cells/microL])
– potentially life-threatening complications of hypereosinophilia
–- likely developing eosinophil-mediated cardiac damage (elevated troponin when cardiac impairment is not yet clinically evident)
–- Thromboemboli: diffuse watershed CNS infarctions or focal CNS thromboemboli (retinal hemorrhages and splinter hemorrhages)
– substantial eosinophil-associated disease on chest CT + clinical symptoms 

HD i.v. glucocorticoids: 1 mg/kg pred tot 1 gr methylprednisolone 1-2 d
- response AEC (drops >50% <24h): most can be stabilized within a week
- remains/minimal response: unlikely to be effective, usually continued until second agent added and response is seen

2e lijn
- Imatinib mesylate – may be effective when steroid-refractory with extremely high counts: more likely to have FIP1L1-PDGFRA-positive HES, less toxic than vincristine
- Vincristine – 1 to 2 mg/m2 intravenously, weekly to monthly, response within hours. Glucocorticoids are continued when vincristine is added.
- Hydroxyurea – orally at an initial dose of 500 to 1000 mg/day and quickly increased to 2000 mg/day as tolerated if the response is suboptimal, a response can take 1-2 weeks 

HES with myeloproliferative features = M-HES
- dysplastic eosinophils
- splenomegaly
- bone marrow findings consistent with chronic myeloproliferative disease
- AF
- cardiovascular involvement
- lack of response to glucocorticoids
- cytogenetic abnormalities
- myelofibrosis
- if mutational analysis not available and treatment required: markedly elevated B12 (>2000 pg/mL), and to a lesser degree elevated tryptase level (>11.5 ng/mL) marker for a FIP1L1-PDGFRA mutation
typically extremely aggressive course: even asymptomatic, promptly imatinib
imatinib mesylate 400 mg/day
plus indien cardiac involvement (elevated serum troponin levels and/or echocardiographic evidence of myocarditis on echocardiography): 1-2 mg/kg prednison 1-4 weken at the same time to prevent cardiac injury to prevent acute necrotizing myocarditis: left ventricular dysfunction and cardiogenic shock, presumably, the mechanism involves massive release of eosinophil granule proteins and subsequent damage to the myocardium, reportedly reversible with prompt institution of systemic glucocorticoids, intensive support, and discontinuation of imatinib
dose reduced to lowest effective dose that maintains molecular remission and continued indefinitely

FIP1L1-PDGFRA mutation (even if asymptomatic) (imatinib: Grade 1B)
– exquisitely sensitive to imatinib: typically, symptoms improve and eosinophil counts normalize within one to two weeks; not respond within two to four weeks, imatinib should be discontinued and other therapies considered
– doses required are lower than in CML for clinical, hematologic (100%), and molecular remission
- 100 mg daily is frequently employed for maintenance when cost is not limiting: proven effective in controlling the eosinophilia and clinical symptoms, although molecular evidence of the FIP1L1-PDGFRA mutation may persist on low-dose therapy 
- alternatively, the dose may be gradually reduced (eg, to 100 mg every other day, then 100 mg twice a week, and then weekly) until the gene transcript reappears at which point the patient should go back to the prior dose and confirm that molecular remission is reachieved
– cardiac symptoms due to structural abnormalities resulting from endomyocardial fibrosis and fixed neurologic deficits may not improve with imatinib therapy
-prolonged remission after discontinued imatinib described: eerst meer studie nodig, keep patients in remission on imatinib for at least two years
– all patients who relapsed after imatinib discontinuation retained their sensitivity
Imatinib-resistant disease
- single base (T6741) substitution in the imatinib-binding portion of the kinase
- allogeneic hematopoietic cell transplantation
- other tyrosine kinase inhibitors: only imatinib proven activity in HES, several agents have activity against PDGFR: dasatinib, sorafenib, and nilotinib

HES with myeloproliferative features in the absence of the FIP1L1-PDGFRA mutation (imatinib: Grade 2C)
- aggressive clinical course
- some cases have mutations involving PDGFRA or PDGFRB with other fusion partners: vast majority translocations involving 5q31-33, including t(5;12) in 78 percent
- imatinib therapy may be considered for first-line therapy in patients presenting with HES and features of myeloproliferative disease (ie, after an initial glucocorticoid challenge, but before any other therapeutic intervention)
- second-line agent with negative F/P test and with myeloproliferative features (9 to 60 percent respond) [9,22,26,44,53,54]
- in ieder geval imatinib voor IFN-a, tenzij zwangerschap
- the starting dose 400 mg daily, dose escalation up to 800 mg daily
– may take longer (up to 4 weeks) and/or require a higher dose of imatinib: no response within one to three months, discontinued and other therapies considered
- alternative tyrosine kinase inhibitor, hydroxyurea, or interferon-alfa. These agents are usually administered in conjunction with glucocorticoids.

myeloproliferative neoplasms with a PDGFRB fusion gene
- Several small reports have described the activity of imatinib
- imatinib (100 to 400 mg daily): response rate of 96%
- within two months, suggesting that a three-month trial was sufficient
- features consistent with chronic myelomonocytic leukemia (CMML)
- peripheral eosinophilia can be marked, eosinophilic end-organ manifestations are uncommon
- PDGFRB-associated myelodysplastic/myeloproliferative neoplasms (MDS/MPN) reviewed separately

symptomatic HES without myeloproliferative features
- o.a. lymphocytic variant HES (L-HES)
- not all patients with HE require treatment at the time of diagnosis.
- asymptomatic patients (hypereosinophilia of undetermined significance [HEUS]): monitored every three (at the beginning) to six months 
- glucocorticoids as initial therapy (Grade 1B): prednisone 20 to 60 mg daily, for one to two weeks
- bij L-HES werkt imatinib niet
- ivermectin prior to the administration of glucocorticoids
- partial or complete remission was achieved in 85 percent at one month
- eosinophilia suppressed: slowly tapered to an alternate-day schedule of the lowest dose that maintains control of the eosinophil count and clinical disease
- snelheid afh snelheid respons en klachten
- no response within a week: dose increased
- patients were able to reduce the dose of glucocorticoids to a median dose of prednisone of 10 mg per day
- not suppressed or dose required excessive (ie, >10 mg/day and/or poor tolerance): second agent added, most commonly used hydroxyurea and interferon-alfa: IFN hogere RR? individualiseren
-- abnormal clonal T cells (lymphocytic variant HES [L-HES]), we suggest the addition of interferon-alfa to glucocorticoid therapy
- fail pharmacologic management with or without the FIP1L1-PDGFRA fusion: allogeneic HCT offers a chance of long-term remission
- eosinophil levels and clinical manifestations monitored weekly at the beginning of therapy

D816V c-kit mutation-positive systemic mastocytosis with eosinophilia
- imatinib werkt niet 

Hydroxyurea 
- 500 to 1000 mg/day and increased to 2000 mg/day as tolerated

Interferon-alfa
monotherapy is not recommended
- Patients with abnormal clonal T cells (L-HES): prevented spontaneous apoptosis in vitro of phenotypically abnormal clonal T cells
- M-HES
doses: 1 million to 8 million units per dose, three to seven times weekly, administered subcutaneously
sample approach: initiate treatment with 1 to 2 million units per injection on alternate days
tolerated: dose increased by 0.5 to 1 million units per injection
gradually increasing to 3 to 4 million units per injection three times weekly
may take several weeks to reach the effective dose and then to observe a response

Pegylated-interferon (peginterferon) (1.5 mcg/kg once weekly) appears equivalent
- the authors reserve peginterferon for patients with stable disease on standard interferon therapy

Cardiovascular disease:
- valve replacement with a bioprosthesis (mech: kans op embolie ondanks antistolling) or repair
- endomyocardectomy
- thrombectomy

Hypersplenism: splenectomy may be indicated, hypersplenism and/or pain due to splenic distension or infarcts

PROGNOSIS
goed: absence of cardiac or neurologic involvement, lower eosinophil counts, and steroid-responsiveness
slecht: findings associated with myeloproliferative disorders
L-HES usually benign lymphoproliferative disorder
ES showed a poor prognosis: mean survival of nine months and a three-year survival of only 12 percent
recenter: 80 percent survival at 5 years and a 42 percent survival at 15 years
FIP1L1-PDGFRA-positive disease treated with imatinib good prognosis