Page 1320 - Hematology_ Basic Principles and Practice ( PDFDrive )

1166 Part VII Hematologic Malignancies

Conventional Cytoreduction and Chemotherapy release of various toxic mediators from eosinophils. However, IFN-α
may also exert an antiinflammatory effect on other cell types that may
Several studies have shown that HU (0.5–2 g/day), is efficacious contribute to tissue damage in HES.
in steroid-nonresponsive patients with HES, including those with
HES I and HES N . In patients with HES I , HU is administered as an
alternative drug or in conjunction with corticosteroids as a steroid- Cyclosporine A (CSA)
sparing medication. A typical starting dose is 500–1000 mg daily. In
combination with corticosteroids, the overall response rate exceeds CSA, an immunosuppressant that interferes with multiple functions
50%. Eosinophil counts begin to decrease 7–14 days after starting and growth of immunocompetent T lymphocytes, has been reported
HU treatment. Depending on the dose, HU may induce cytopenias. to be effective in a subset of patients with HES. The goal of CSA
Otherwise, HU is usually well tolerated unless very high doses are treatment in HES is to inhibit production of eosinophilopoietic
administered, and is therefore also used as a palliative drug in HES N cytokines, including IL-5, by T cells in these patients. CSA has been
patients resistant to targeted drugs and chemotherapy. However, not used as a single agent or in conjunction with low-dose corticosteroids.
all patients with HES may respond to HU. Historically, a number of In those with steroid-sensitive disease, CSA may act as a steroid-
cytotoxic agents have been used to treat HES refractory to steroids sparing agent. However, good responses may only be seen in distinct
and HU, including vincristine, etoposide (VP-16), and chlorambucil. variants of HES, namely those HES variants where T-cell activation
However, each of these agents can produce cytopenias and other side is a causative etiology. Another important point is that efficacy has
effects, and their use should be limited to select patients with HES in so far only been described for CSA in short-term–treated HES
whom neoplastic cells develop resistance against other agents includ- patients (10 months), whereas long-term efficacy has not been
ing HU. In patients with advanced, resistant CEL or AEL, but also determined so far. In each case, the side effects and immunosuppres-
in patients with AML-eo, other advanced myeloid neoplasms with sive effects of CSA have to be taken into account. In patients with
FGFR1 rearrangement (8p11 myeloproliferative syndrome), intensive HES N , CSA should not be administered.
polychemotherapy and allogeneic HSCT are usually recommended.
These chemotherapy regimens are usually the same as applied in
patients with refractory leukemias without HE/HES. Chemotherapy Targeted Treatment Approaches Using Tyrosine
before allogeneic HSCT is often a preferable initial approach for Kinase Inhibitors
two reasons: first, debulking may result in remission, and patients
in remission have in general a better overall outcome after allogeneic Several different oncogenic kinases have been detected in primary
HSCT. In addition, chemotherapy can provide some indication as to eosinophilic disorders (mostly CEL and MPN-eo) and serve as targets
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whether a patient can tolerate intensive therapy. On the other hand, of therapy. The most relevant and most frequent target kinase
multiple cycles of chemotherapy increase the risk of infections, which detectable in patients with CEL is F/P. This fusion gene product is
may be problematic in the context of a planned allogeneic HSCT. a target of imatinib and also sensitive to other TKIs, such as nilotinib,
dasatinib, PKC412 (midostaurin), or ponatinib. A number of other
oncoproteins may also serve as targets of imatinib and are detectable
Interferon-α in primary eosinophil disorders. Most of these fusion genes involve
PDGFRA or PDGFRB, whereas FGFR1 mutants are imatinib resis-
IFN-α has been used for the treatment of HES for more than 25 tant. The hematologic benefit of imatinib in F/P-positive neoplasms
years, both as monotherapy and in combination with other agents. and PDGFRB-rearranged neoplasms has been confirmed in several
A number of studies have shown that this type of therapy can suc- clinical trials. 26,27 Therefore, imatinib is regarded as standard first-line
cessfully counteract HE and HES in patients in whom treatment with therapy in these patients. Given the poor prognosis in patients with
prednisone and HU has failed. Response rates to IFN-α vary depend- overt organ damage (HES N ), patients with an F/P+ neoplasm or
ing on the underlying disease and dose, but may be approximately another mutation involving PDGFRA or PDGFRB genes should be
50% when used as monotherapy and 75% in combination with other treated with imatinib, even in the absence of end-organ damage, in
agents. Usually, therapy is initiated at a dose of 1 million units three order to prevent any HES occurrence. Although the optimal dosing
times a week, and is titrated up to 4 million units three times weekly. strategy for imatinib has not been fully defined, a number of studies
In the responding patients, eosinophil counts decrease, and improve- have shown that a daily dose of 100 mg appears to be sufficient to
ment in splenomegaly and hepatomegaly has been reported. Moreover, induce complete hematologic and molecular remission in most
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the risk of cardiac and thromboembolic complications can be reduced patients. Moreover, 100 mg imatinib/day appears to be a safe
by treatment with IFN-α. Finally, mucosal ulcerative lesions and approach in all patients, including those who suffer from cardiac
other skin manifestations may substantially improve. The unpro- involvement. Therefore, 100 mg/day is regarded a standard dose of
cessed and the pegylated form of IFN-α may be equally effective. initial therapy with imatinib in F/P+ CEL. However, in a few patients
However, despite efficacy, the administration of IFN-α is problematic with PDGFRA- or PDGFRB-rearranged neoplasms, higher doses of
because of side effects. These side effects are often dose dependent imatinib (400 mg daily) are required to induce a durable remission.
and include fever, a flu-like syndrome, fatigue, impotence, depres- In those who enter a hematologic and molecular remission, imatinib
sion, suicidal ideation, and psychosis. In addition, IFN-α therapy is usually maintained, as discontinuation is often followed by a
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may lead to exacerbations of autoimmune disorders, such as auto- relapse. However, it remains unknown whether all patients need to
immune thyroiditis, psoriasis, ulcerative colitis, and others, but also continue on their initial dose on a life-long basis. In fact, it has been
to exacerbation of depression or other psychiatric diseases. Other described that many of these patients do not relapse when lowering
serious adverse events observed with IFN-α include excessive sup- the dose of imatinib or even when imatinib is discontinued. In other
pression of blood counts, retinopathy, sarcoidosis, and left-sided heart patients, however, resistance against imatinib may occur. In relapsing
failure. All these (potential) side effects have to be taken into account, patients, F/P point mutations associated with decreased (or loss of)
especially when prescribing IFN-α on a long-term basis at relatively drug-binding capacity may be detected. For these patients, novel
high doses. On the other hand, IFN-α is non-mutagenic and is TKIs, such as sorafenib, nilotinib, midostaurin, or ponatinib may be
considered a drug that can be prescribed even during pregnancy. The considered. The most commonly detected mutant, T674I, is sensitive
mechanism of action of IFN-α is not well understood. Receptors for in vitro to a number of different TKIs, including PKC412, sorafenib,
this cytokine are expressed on multipotent hematopoietic progenitor and ponatinib. Other secondary mutations in F/P+ disease, such as
cells, eosinophil-committed precursors, and mature blood eosino- D842V, are very rare. However, once these secondary mutations
phils. Therefore, in contrast to corticosteroids, IFN-α works in HES occur during treatment with multiple TKIs, they usually exhibit
patients with diverse etiologies, including HES L, but also in HES N pan-resistance. In fact, durable responses to TKIs with either the
and even in HES I . IFN-α inhibits eosinophil activation and the T674I or D842V mutation are not generally observed, and especially