Page 1321 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 71 Eosinophilia, Eosinophil-Associated Diseases, Eosinophilic Leukemias, and the Hypereosinophilic Syndromes 1167

the F/P D842V mutant is resistant to almost all available TKIs. More surface receptors expressed by eosinophils are currently in preclinical
recently, it has been described that ponatinib can kill neoplastic development. The epidermal growth factor-like modul-containing,
eosinophils exhibiting all types of F/P mutations in vitro at clinically mucin-like hormone receptor 1 (EMR1) is expressed specifically on
achievable drug concentrations. Whether this also holds true in vivo human blood eosinophils and may serve as a potential target of
in patients with TKI-resistant CEL or acute leukemias exhibiting this therapy. A novel, humanized afucosylated anti-EMR1 IgG1 anti-
F/P mutant, presently remains unknown. Another approach in body has recently been shown to augment NK cell-mediated killing
patients with TKI-resistant eosinophil neoplasms is to apply cytore- of eosinophil granulocytes. Benralizumab is an antibody directed
ductive agents (IFN-α, HU) or experimental drugs. In patients who against the IL-5 receptor on eosinophils and their precursor cells.
transform to an acute leukemia, polychemotherapy and allogeneic So far, benralizumab has been tested in normal subjects and patients
HSCT is usually recommended. with asthma, and is currently being tested in patients with HES.
A number of different markers have been proposed for the moni- BM studies have shown that this antibody induces a remarkable
toring of treatment responses in patients with F/P+ CEL. A close depletion of eosinophils and their precursor cells. It is noteworthy
hematologic follow-up is recommended for the first weeks of therapy, that the IL-5 receptor is also expressed on basophils, albeit at lower
where a rapid decline in eosinophils (and leukocytes) is usually levels. Another interesting target receptor is Siglec-8. This antigen is
observed, and is regarded a good prognostic sign. After a few months, expressed on eosinophils and mast cells, but not on neoplastic stem
the BM should be examined in order to document and confirm the cells. Remarkably, Siglec-8 crosslinking induces eosinophil apoptosis
hematologic response. A complete remission is obtained in most and inhibits IgE-mediated mast cell activation, thereby providing a
patients, even if the initial BM revealed marked involvement at common mechanism to limit inflammation caused by the coexistence
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diagnosis, including fibrosis and/or increased blast cells. In patients and functional interactions of these cells. Whether this concept is
with a complete hematologic remission, molecular monitoring and a clinically effective, remains at present unknown. Since Siglec-8 is not
repeat PCR and FISH analysis is recommended in order to define expressed on immature eosinophilic progenitor cells or neoplastic
the molecular response. Quantitative measurement of the F/P mRNA stem cells, the drug may not be useful in eosinophil malignancies.
burden by reverse-transcriptase-PCR is available in many centers and By contrast, Siglec-3 (CD33), another established drug target, is dis-
can be employed to define the depth of the remission. In those with played by normal and neoplastic eosinophils and even by neoplastic
an initially elevated serum tryptase, serial determinations of tryptase stem cells. Gemtuzumab ozogamicin is a humanized CD33 antibody
are also useful to document the response to imatinib or other TKIs. conjugated with calicheamicin. Although the drug is highly effective
Finally, in those with end-organ damage, including cardiac disease, in targeting myeloid cells and their progenitors in AML, the drug has
reinvestigation of all involved organ systems is recommended to been withdrawn from the market because of toxicity issues. However,
demonstrate potential reversion of end-organ damage. In high-risk when used at limited doses and at reasonable time intervals, the
patients (e.g., cardiac history), echocardiography and troponin as well toxicity of such antibodies may be acceptable.
as B-type natriuretic peptide levels before initiating therapy may be Another approach is to target eosinotropic cytokines using specific
recommended to gauge the potential risk. antibodies, which is a strategy that is recommended for patients with
Although imatinib and other TKI therapies in CEL patients is reactive HE and HES (HES R ) as well as HES L , where overproduction
generally well tolerated, all these agents can produce severe side effects. of such cytokines is known to play a pathogenetic role. These agents
Even imatinib may produce severe side effects, especially when applied include antibodies directed against IL-5, against eotaxin, or other
to HES patients with cardiopathy at 400 mg daily. In fact, in a few cytokine agonists. Mepolizumab is a fully humanized IgG1 antibody
cases severe left ventricular dysfunction has been reported soon after that binds IL-5 and prevents its binding to the IL-5 receptor alpha
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initiation of imatinib therapy. Therefore, close monitoring of these chain. In 2008 a randomized, double-blind, placebo-controlled trial
patients is recommended during this time period and prophylactic showed that mepolizumab is effective as a corticosteroid-sparing agent
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steroids (during the first week of treatment) should be considered. The in patients with severe (drug-resistant) HES R . Adverse events were
second- and third-generation TKIs used to treat CML and CEL may tolerable and similar in the treated and in the placebo groups. Mepo-
also produce severe side effects, and many of them may affect the lizumab has been recently FDA approved for the treatment of eosino-
cardiovascular system or metabolic parameters, which is relevant clini- philic asthma and tested in HES patients in clinical trials. Reslizumab
cally in the context of HES. The most relevant side effects of dasatinib is a humanized IgG4 anti IL-5 antibody that is currently being tested
are pleural and pericardial effusion, and the most relevant adverse in clinical trials for eosinophilic esophagitis and in pediatric patients
events observed with nilotinib and ponatinib are arterial occlusive for eosinophilic asthma, but it has not been studied in the context of
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events that may occur as a result of a rapidly progressive form of HES. Initial results suggest that the drug is effective in reducing
atherosclerosis. In the case of nilotinib, increasing fasting glucose levels eosinophil counts and clinical symptoms. Bertilimumab is a human
and cholesterol levels have been documented during therapy. anti-eotaxin-1 antibody that is currently being tested in a phase II
clinical trial for ulcerative colitis, but has not been tested yet in HES
patients. Together, more controlled clinical trials in HES patients are
Targeted Antibodies needed in order to learn which antibodies directed against eosinophilic
receptors and eosinotropic cytokines are most effective in patients with
A number of targeted antibodies and antibody–toxin conjugates have primary or reactive eosinophil disorders and HES.
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been considered for patients with HE-related disorders and HES.
These antibodies are either directed against (neoplastic) eosinophils
and their precursor cells or against eosinotropic cytokines, such as Leukapheresis
IL-5. Antieosinophil antibodies are considered useful in neoplastic
states and should ideally be directed against both eosinophils and Leukapheresis has no defined role in the management of HES.
their precursor cells, or even neoplastic stem cells. One such anti- However, leukapheresis may be useful in emergency situations for
body is alemtuzumab. This humanized antibody is directed against patients with excessively high eosinophil counts. Since cell counts
CD52 (= Campath-1), a surface receptor expressed on neoplastic rebound rapidly to pretreatment levels, such a maneuver should
stem cells in various leukemias as well as on eosinophils and their always be combined with cytoreductive therapy in order to keep
precursor cells. Alemtuzumab therapy in patients with drug-resistant eosinophil counts under control.
eosinophil disorders has been reported in a limited number of
studies. In about 80–90% of the patients the drug induced remis-
sion. However, in over 80% of these patients relapses occurred after Anticoagulation and Antiplatelet Agents
cessation of therapy. In addition, alemtuzumab produced substantial
side effects, including severe hematological toxicity with subsequent Thromboembolic complications may be life-threatening in HES
opportunistic infections. Several other antibodies directed against cell patients. Therefore, prophylactic anticoagulation may be considered