in many ways, this form may follow an acute course despite the absence
of predominantly blast forms in the peripheral blood. The decision to list
CEL and HES together does not imply that the WHO considers all cases of
HES to be clonal myeloproliferative diseases. Rather, it addresses the
problem that, in practice, it may be virtually impossible to distinguish
between clonal eosinophilia and eosinophilia secondary to abnormal cytokine
production for which no etiologic basis is recognizedref1,
ref2,
ref3.
The diagnosis of CEL or HES can be made only after a number of infectious,
inflammatory, and neoplastic diseases known to be associated with eosinophilia
(including CML, AML with inv(16), other CMPDs, T-cell lymphoma, Hodgkin
lymphoma, and others) have been excluded. Then, if there is no evidence
for clonality, the diagnosis of HES is preferred, whereas the finding of
a clonal myeloid abnormality would support the diagnosis of CELref.
HES are a heterogeneous group of disorders characterized by marked blood
and tissue eosinophilia resulting in a wide variety of end organ manifestationsref.
Table of contents :
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.
Although large series based on Chusid’s criteria have consistently shown
that skin, heart and nervous system involvement are most common, any organ
can be affected. Furthermore, the clinical manifestations appear to differ
depending on the underlying etiology of the eosinophilia,
ataxia, eosinophilic
meningitis,
lymphadenomegaly,
vasculitis,
ascitis,
pancreatitis,
cholangitis,
Budd-Chiari
syndrome
(F/P), a fusion tyrosine kinase associated with most cases of imatinib-responsive
HESref.
Although patients with PDGFRA-associated HES occasionally have cytogenetic
abnormalities, the vast majority of cases are due to a small interstitial
deletion in chromosome 4, del(4)(q12q12), that is undetectable by
standard cytogenetics. The breakpoints in FIP1L1 are variable but are
typically located in a 40-kb region spanning introns 7–10 of FIP1L1. In
contrast, the breakpoints in PDGFRA appear to be restricted to a region
of exon 12 that contains the WW-like region of the juxtamembrane domain,
thus retaining the entire kinase domain of PDGFRA in all cases. FIP1L1
(f) exons 9 to 13 (formerly described as 7a, 8, 8a, 9 and 10ref):
level
translocations on chromose 8p11 fuse the FGFR1 C-terminus catalytic domain
with unrelated proteins :
.
ZNF198-FGFR1 induces EMS-like disease in mice, with myeloproliferation
and T lymphoma arising from common multipotential progenitors. Mutation
of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying
PLC-g1 as a downstream effector. Bcr-FGFR1 binds
Grb2 via Bcr Tyr177 and induces CML-like leukemia in mice, whereas Bcr-FGFR1/Y177F
lacks Grb2 binding and causes EMS-like disease. These results implicate
different signaling pathways originating from both kinase and fusion partner
in the pathogenesis of CML and EMSrefref,
although occasional patients may achieve complete cytogenetic remission
with IFN-g based therapy.
,
AML,
or lymphoma that is generally of T-cell phenotyperef1,
ref2.,
restrictive
lung disease
and mucosal ulcerations, appear to occur predominantly in patients with
PDGFRA-associated disease
,
T lymphoma or hypereosinophilic syndrome (HES), but not in patients with
a parasitic infection. A significant reduction in the sCD23 levels was
found after treatment, with a parallel decrease in eosinophil counts and
in sCD25 levels, a marker of disease activity in HES. The lack of increase
in membrane CD23+ B cells in eosinophilic patients together
with the detection of sCD23 in eosinophil supernatants suggest that activated
eosinophils present in eosinophilia-associated disorders can release soluble
molecules cross-reacting with CD23ref.
is rare, but does occurref1,
ref2.
)
that are indistinguishable from c-kit mutation-driven systemic mast cell
diseaseref.
It is extremely important to distinguish these patients from those with
c-kit mutation-driven disease, as 816V, the most common c-kit mutation
associated with systemic mastocytosis, is resistant to imatinib. Conversely,
some cases of HES with features of myeloproliferative disorders (up to
20% in our experience) are not associated with the F/P mutation. Although
occult leukemias have been described in a few instancesref,
the etiology of most of these cases remains unknown, and the response to
imatinib is variable.
,
by clonal populations of phenotypically abnormal, activated Th2
lymphocytesref.ref
are also common; whereas tissue fibrosis, including endomyocardial
fibrosis
and myelofibrosis, are rarely seen
appears to be most common in this subgroup of patients and should be suspected
in the setting of increasing numbers of aberrant T cells and/or the development
of lymphadenopathy. 2 features that appear to be associated with an increased
likelihood of progression to lymphoma are the CD3–CD4+CD8–
surface phenotype and the presence of cytogenetic abnormalities (6q deletions)ref.,
produced by the T-cell clone. In patients whose primary complaint is swelling
and/or weight gain, it is useful to measure eosinophil counts every 3 days
for several weeks off therapy. Oftentimes, the periodicity is missed because
of intermittent steroid use and measurement of eosinophil counts only when
symptoms are present. Although some patients with this syndrome ultimately
progress to HES and/or develop clonal populations of lymphocytesref,
the unique clinical presentation, including an absence of end organ involvement,
is suggestive of a common and distinct etiology in this clinical subgroup
of patients. Increased numbers of immature CD4+CD+
T cells and NK cells were observed in peripheral blood during the asymptomatic
period. The latter population significantly decreased during the flare.
Th1 cells were decreased in both asymptomatic and, more markedly,
during the attack with respect to healthy subjectsref.–like
syndrome in which vasculitis cannot be demonstrated despite appropriate
biopsies
have been and continue to be a mainstay of treatment in HES. With the exception
of F/P-associated HES, steroids remain the first-line treatment for most
patients. Steroids should also be used in addition to imatinib in patients
with F/P-associated HES and evidence of myocarditis, as suggested by EKG
or echocardiographic assessment or the presence of an elevated serum troponin
levelref.
Although the most appropriate initial steroid dose and the duration of
steroid therapy have not been studied, it seems prudent to start with moderate
to high doses ( 40 mg prednisone equivalent daily) and to taper very slowly
following the eosinophil count closely. Using this approach, most, but
not all, patients will respond initially to steroid therapy, and some will
be able to be maintained on low doses for long periods. Over time, however,
the toxicities of steroid therapy become limiting and alternative therapies
must be used.ref,
vincristine,
and cladribrine
+ cytarabineref,
have been used for the management of steroid-refractory HES. Of these,
hydroxyurea has been the most extensively studied and, at doses of up to
2 g/day, is associated with few side effectsref.
Although some patients will respond to low-dose hydroxyurea therapy, many
require higher doses to adequately control the eosinophil count. As the
dose increases, hematologic and gastrointestinal side effects become common,
limiting the utility of hydroxyurea in the treatment of HES. Furthermore,
hydroxyurea cannot be used to acutely lower the eosinophil count since
a therapeutic effect is generally not achieved for up to 2 weeks.,
cyclosporine
and intravenous
immunoglobulin,
have been shown to have a therapeutic effect. Of these, interferon- has
been the most successful with stable responses achieved with relatively
low doses (1–2 mU/day) over prolonged periods of timeref.
Rarely, patients have remained in remission for extended periods of time
following cessation of interferon therapy, suggesting that interferon may
be curative in a small subset of individuals. Even at low doses, systemic
toxicity is common with interferon therapy and can be dose-limiting. Low-dose
hydroxyurea (500 mg daily) appears to potentiate the effect of interferon-
on eosinophils without increasing toxicity and can be used in these situations.
The use of a second agent in combination with IFN-a
is recommended in L-HES on the basis of in vitro data demonstrating
inhibition of apoptosis of clonal CD3-CD4+ T cells
by interferonref.
In this instance, steroids are the preferred second agent because of their
proapoptotic effect.,
in patients in whom the fusion gene has been demonstrated or in selected
patients with the characteristic clinical and laboratory features of this
HES subtype, a number of controversies remain with respect to the appropriate
dose and duration of imatinib therapy and the use of imatinib in other
subgroups of patients with HES. Imatinib response rates in F/P+
patients approach 100%ref,
with only 2 reported cases of acquired drug resistance, both associated
with a T6741 substitution in the ATP-binding domain of PDGFRA that
is analogous to the T3151 mutation in ABL seen in imatinib-resistant CMLref1,
ref2.
Clinical responses in F/P+ patients are rapid, with normalization
of eosinophil counts generally occurring within 1 week of initiation of
treatment and reversal of signs and symptoms within 1 month. The exception
is cardiac involvement, which is irreversible unless treatment is begun
before fibrosis leads to permanent anatomic alterationsref1,
ref2.
Although side effects of imatinib therapy are generally mild and rarely
lead to discontinuation of therapy, cardiac decompensation has been observed
in at least one patient treated with imatinib, and has led to the recommendation
that patients be screened for elevated troponin levels prior to therapy
and pre-treated with steroids if levels are elevatedref.
Clinical remission and normalization of eosinophil counts has been reported
in patients treated with imatinib at doses as low as 100 mg daily; however,
some patients will continue to have molecular evidence of the mutation
at this dose. Our experience suggests that all F/P+ patients treated with
400 mg daily achieve durable clinical, hematologic and molecular remissionref.
In view of the data from CML, which suggest that clinical relapse is more
common in patients with detectable residual disease, it seems prudent to
begin
imatinib treatment at 400 mg to achieve molecular remission and to
then decrease the dose slowly following closely for evidence of molecular
relapse. The utility of imatinib therapy in patients without the F/P mutation
remains to be determined, although some patients have demonstrated a responseref.
In general, these responses have been slower and have required higher imatinib
doses than those in patients with F/P-associated disease. Imatinib does
not appear to be useful in treating patients with the L-HES and should
not be used as first-line therapy in these patientsref.
Although imatinib is the only tyrosine kinase inhibitor with activity against
PDGFRA that is commercially available at this time, additional agents currently
in development are likely to be effective in PDGFRA-associated HES. One
of these, PKC412, has already been demonstrated to be effective against
the T6741 resistance mutation in vitroref
therapy for HES has a number of unique advantages related to the specificity
of IL-5 for the eosinophil lineage. Preliminary studies using two different
anti-IL-5 antibodies, SCH55700 and mepolizumab, demonstrated a dramatic
and prolonged lowering of the peripheral eosinophil count in response to
a single dose of antibody in a majority of HES patients regardless of the
underlying etiology or baseline IL-5 levelref.
The therapy was extremely well tolerated, although a rebound in symptoms
and eosinophilia associated with an increase in serum IL-5 levels was noted
in one study as antibody levels decreasedref.
The safety and efficacy of anti-IL-5 therapy as a steroid-sparing agent
in HES is currently being assessed in a large, double-blind, placebo-controlled
study of mepolizumab.
has been used successfully in the treatment of HESref
and should be considered in patients with F/P+ disease who become
resistant to or are unable to tolerate imatinib therapy and in F/P–
patients with severe progressive end organ damage once standard therapies
have been exhausted.
mesylate 100 mg/day => evaluation of response after 1 month => eventually
increase dose up to 400 mg/day => if no response IFN-a
3 MIU/day a.d. => alemtuzumab
=> prednisone/cladribrine
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