Nilotinib and Imatinib Are Comparably Effective in Reducing Growth of Human Eosinophil Leukemia Cells in a Newly Established Xenograft Model

We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL) to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL

Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Immunologic Adverse Effects of Biologics for the Treatment of Atopy

The use of biologic agents as therapies for atopic diseases such as asthma and atopic dermatitis has increased greatly in recent years. The biological agents used to treat atopic diseases are for the most part monoclonal antibodies that suppress the immune response and reduce inflammation by targeting particular cytokines or other molecules involved in Th1, Th2, or Th17 immune reactions. Various side effects and rare complications have been reported from these agents. In this review, we discuss mechanisms of various adverse effects for the biologic agents currently in use or in development for atopic and inflammatory diseases. Monoclonal antibodies targeting the Th1 and Th17 pathways have been associated with significant side effects, partially due to their ability to cause significant impairment in immune responses to pathogens because of the immunologic alterations that they produce. Biologicals targeting Th2-mediated inflammation have had fewer reported side effects, though many are new and emerging drugs whose adverse effects may remain to be fully elucidated with more use. Therefore, continued long-term safety monitoring is required. As with all therapies, the risks associated with side effects of biologics must be balanced against the benefits these drugs offer for treating atopic diseases. One of the most apparent benefits is the steroid-sparing effect of well-chosen biologic therapy used to treat severe atopic disease. In contrast with the quite favorable safety profile of currently available biologics that target the Th2-mediated immune response, chronic systemic corticosteroid use is associated with significant side effects, many of which impact the majority of patients who are placed on long-term steroid therapy

Emerging biologics for the treatment of chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a prevalent chronic inflammatory disease of the nasal and paranasal cavities and is known to seriously impair quality of life in affected patients. CRS appears to be a heterogeneous group of diseases with different inflammatory and remodeling patterns, suggesting that not only different clinical phenotypes but also pathophysiological endotypes occur. CRS with nasal polyps (CRSwNP) is considered a more severe phenotype, especially when associated with comorbid asthma, as patients having this condition often do not respond to conventional treatment, including topical and systemic corticosteroids or surgery. Recently, studies with biologic agents have shown various effects in severe airway disease; specifically in Th2-biased CRSwNP, these effects were very promising. The greatest challenge for the future is to define the different endotypes of CRSwNP using easily accessible biomarkers to select the patients who have the best chance of a positive therapeutic response to innovative approaches