Page 1322 - Hematology_ Basic Principles and Practice ( PDFDrive )

1168 Part VII Hematologic Malignancies

in patients with HES, especially in those in whom the risk for improvement in cardiac function, provided the underlying disease
thromboembolic complications is high, such as in patients with a F/ and the related HE can be kept under control.
P+ disease, cardiac involvement, or neurologic symptoms. In patients
with overt HES and associated thromboembolic events, anticoagula-
tion is a standard approach. Commonly used agents are warfarin, SUMMARY AND FUTURE PERSPECTIVES
antiplatelet agents, and heparin. The efficacy of these drugs has not
been formally established in HES, and some of the patients may The diagnosis, classification, and management of patients with
continue to have thrombotic events, despite adequate anticoagula- persistent HE remains a challenge in clinical practice, especially
tion. Therefore, it is always important to also treat the underlying when no underlying disease is identified and/or HE-related organ
disease if possible, in order to stop the thromboembolic state. damage (HES) develops. Because of disease heterogeneity and the
power and specificity of novel markers and targets, each case needs
to be investigated and managed using the full battery of diagnostic
Splenectomy markers and assays, and according to contemporary diagnostic and
therapeutic algorithms. 3,14 Depending on the overall situation, initial
Splenectomy is usually not required in patients with MPN-eo, AEL, investigations include BM studies (histology, cytology, and cytogenet-
or CEL. However, in rare cases, splenomegaly has been performed to ics with FISH), molecular analyses, immunologic parameters, and
correct hypersplenism-related cytopenias, or to avoid splenic infarc- a complete staging of all potentially involved end-organ systems.
tion and pain induced by capsular distention. In benign disease variants, the course can sometimes be monitored
without specific treatment. However, in patients with (1) advanced
Allogeneic Hematopoietic Stem Cell hematopoietic neoplasms, (2) overt HE-related end-organ damage
(HES), (3) an active underlying (systemic) immunologic, infectious,
Transplantation or allergic disease, (4) evidence of a specific clinical syndrome with
systemic organ involvement, or (5) organ-restricted marked inflam-
Although the experience with allogeneic HSCT in patients with mation associated with eosinophilia, such as eosinophilic colitis or
advanced BM neoplasms accompanied by HE (with or without HES) eosinophilic pneumonia, specific treatment needs to be initiated. In
is quite limited, allogeneic HSCT should be considered in certain reactive conditions, symptomatic treatment and corticosteroids are
groups of patients, especially those who are (1) young and fit, (2) usually administered. In addition, it is of utmost importance to treat
have a suitable transplant donor, and (3) have a progressive and and eradicate (or control) the underlying disease, such as a NHL,
treatment-resistant form of an underlying myeloid or lymphoid helminth infection or IgE-dependent allergy, in these patients. Such
neoplasm. More or less definitive indications in this regard include treatment is often followed by complete resolution of reactive HE and
FGFR1-rearranged neoplasms, drug-resistant cases of AEL or CEL, of the related HES. In treatment-resistant patients in whom reactive
chemotherapy-resistant peripheral T-cell lymphomas accompanied by eosinophilia is likely to be triggered by eosinophilotropic cytokines
HE/HES, and treatment-resistant (progressive) cases of MPN-eo, such as IL-5, anti-cytokine therapy, such as mepolizumab, may be
AML-eo, or MDS-eo. If possible, debulking therapy should be considered. This drug has shown promising results in patients with
introduced prior to conditioning and HSCT, especially when the steroid-resistant reactive HES and other HE-related conditions, such
burden of neoplastic cells is high or excessive. Such debulking may as eosinophilic esophagitis. In advanced hematopoietic neoplasms,
be performed with polychemotherapy or with experimental drugs. treatment with targeted drugs or less specific cytoreductive agents is
Several but not all transplanted patients may enter a complete remis- recommended. In F/P+ patients and those with related PDGFR fusion
sion. Transplant-related mortality rates may not be higher compared genes, imatinib is an undisputable standard of therapy. For patients
with age-matched patients with other advanced hematopoietic neo- with imatinib-resistant F/P+ CEL or MPN-eo, MPN-eo without a
plasms. As in other BM neoplasms, age, comorbidities, and the PDGFR mutant, or HE-related malignancies expressing FGFR1 or
disease status are major risk factors concerning survival and transplant- JAK2 fusion genes, novel TKIs are available. In patients in whom
related mortality. In this regard, it should be noted that the presence secondary mutations in F/P are detectable, novel PDGFR-targeting
of HES-related organ damage, such as overt cardiomyopathy or TKIs such as ponatinib may work. In cases with FGFR1-rearranged
thromboembolism, but also neuropathies or GI disease, may count neoplasms, novel FGFR blockers may overcome resistance, and in
as relevant comorbidities, and if severe in nature, may represent a patients with JAK2-mutated MPN-eo, ruxolitinib may elicit clinically
contraindication to allogeneic HSCT. In those who are successfully meaningful responses. In rapidly progressive and/or drug-resistant
transplanted, the clinical course may be complicated by graft-versus- cases, high-dose chemotherapy and allogeneic HSCT need to be
host disease requiring treatment with corticosteroids, cyclosporin-A, considered. In patients who are TKI resistant and not eligible for
or/and other immunosuppressive drugs. Little is known about long- allogeneic HSCT, HU, other cytostatic agents, or IFN-α serve as
term outcomes after allogeneic HSCT. In smaller case series and palliative drugs. Current research aims at exploring the evolution
single cases reports, long-term survivors have been described. of HES and at defining mechanisms regulating the development of
However, relapses have also been reported in most groups of patients. HE-mediated end-organ damage, which should lead to more selective
and improved therapies in the future. Clinically relevant targets for
these efforts are likely to include (1) neoplastic stem cells produc-
Cardiac Surgery ing eosinophil neoplasms such as CEL or MPN-eo, (2) molecular
targets created specifically by neoplastic cells, such as mutant forms of
In a subset of patients with HES, surgical intervention of cardiac PDGFRs or FGFRs, (3) eosinophilotropic cytokines and their recep-
lesions is required. Interestingly, such intervention does not appear tors, (4) underlying T-cell clones triggering eosinophil expansion
to carry a major risk for disease recurrence at the operative sites. and/or activation through production of eosinopoietic cytokines, (5)
Indications for surgery include a significant compromise of valvular adhesion receptors and other molecules mediating eosinophil homing
function and the presence of a clinically significant thrombotic and redistribution, such as VLA-4, and (6) signaling molecules
mass. Cardiac surgery has the capacity to provide a substantial responsible for cytokine-dependent or -independent eosinophil
clinical and quality-of-life benefit in these patients. In fact, success- proliferation, migration, adhesion, or/and activation. Another aim
ful mitral valve and/or tricuspid valve repair or replacements have for the future is to better understand cellular interactions and related
been reported in HES patients in several studies. For mitral valve molecular mechanisms underlying HE-induced organ damage (HES)
replacements, mechanical valves have proven problematic because of in various organ systems. There is hope that an improved knowledge
recurrent thrombosis despite adequate anticoagulation, suggesting of mechanisms regulating end-organ damage will lead to the develop-
the use of porcine valves whenever possible. HES patients who have ment of new treatment concepts and better therapies for patients
received valve replacements have generally experienced long-term with HES.