Search

Background: Chronic Graft-versus-Host Disease (cGVHD) can impact quality of life, especially in patients with oral involvement. Half of the patients with cGVHD do not respond to first-line therapy with corticosteroids and calcineurin inhibitors. Ruxolitinib is effective in steroid-refractory (SR)-cGVHD cases, but the long-term effects of ruxolitinib on the oral mucosa are unknown. Objective(s): This study aims to assess the effect of ruxolitinib on the oral mucosa of SR-cGVHD patients with oral involvement. Materials and methods: An observational longitudinal patient study was conducted in 53 patients with SR-cGVHD and oral involvement who were treated with ruxolitinib. The baseline condition of the oral mucosa was compared to its condition at 4 and 12 weeks after starting ruxolitinib. Results: The overall response was 81% (43/53), with a complete response in 53% (28/53) and partial response in 28% (15/53) after 12 weeks (p < 0.001). Men and patients concurrently using immunosuppressive therapy responded better than women (p = 0.005) and patients with ruxolitinib monotherapy (p = 0.02), respectively. At a longer follow-up (median 20 months), oral symptoms were comparable to the 12-week symptoms (p = 0.78), regardless of ruxolitinib use (p = 0.83). Conclusion: Ruxolitinib treatment of SR-cGVHD patients with oral involvement was associated with a significant response of the oral manifestations at 12 weeks. Clinical relevance: The oral mucosa of SR-cGVHD patients is likely to improve after 4 and 12 weeks of ruxolitinib treatment. Symptom severity at baseline does not affect the response of the oral mucosa. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis, collectively referred to as myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in their 6th or 7th decade of life, and only some of these patients have been considered suitable transplantation candidates. The development of reduced-intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK) 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life for MF patients. These drugs may also affect the decision regarding, in particular, the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplantation candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF. [ABSTRACT FROM AUTHOR]

Intracellular Janus kinases (JAK) signaling pathway participates in many cells during its activation, proliferation, differentiation and death; particularly in interleukins mediated cellular functions whose direct or indirect involvement in autoimmune diseases has been demonstrated. Numerous therapeutic assays have been developed since 2007 using JAK inhibitors; the first ones were done in leukemia cases and then for controlling autoimmune diseases, all together with promising results, similar to those obtained with anti-tumor necrosis factor (TNF) but without its side effects. In psoriasis, the first successful results obtained in murine models, using the prodrug R348 (JAK 1 and JAK 3 inhibitor), allowed progress to Phase 1 and 2 placebo-controled, double blind clinical trials, with oral tofacitinib, a JAK 3 inhibitor. The results, after a strict management protocol of drug administration and patient monitoring based on universally accepted clinical criteria, showed improvement in almost all clinical and biological manifestations, with reversible side effects throughout treatment, expressed as lipid metabolism changes and neutropenia. Finally, in 2012, the agent INCB018424, a small molecule inhibitor of JAK for topical application drastically decreased between weeks 4 and 8 the skin erythema, scaling, and thickness, by blocking signaling JAK / STAT mediated Interferon Gamma (IFN-Ɣ) in keratinocytes. When finished, these Phase I, and Phase III clinical trials, JAK inhibitors may represent a true transition in the therapeutic approach of psoriasis. [ABSTRACT FROM AUTHOR]

Essential thrombocythemia, polycythemia vera, and myelofibrosis belong to the class of Bcr-Abl negative hematologic neoplasms, which arise in part from varying Janus kinase-2 (JAK2) cellular deregulation. With the development of novel tyrosine kinase inhibitors capable of successfully inhibiting JAK in vivo, an influx of JAK2 inhibitors has come under clinical investigation. Ruxolitinib (Jakafi®; Incyte Corporation, Wilmington, DE, USA) was the first of these compounds to gain US Food and Drug Administration approval in late 2011 for the treatment of intermediate- and high-risk myelofibrosis. Two Phase III clinical trials - Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I and -II (COMFORT-I and -II) - played key roles in the US Food and Drug Administration approval of ruxolitinib with successful demonstration of spleen reduction and symptom palliation. Well tolerated in most patients, common side effects include cytopenias and gastrointestinal toxicities. The majority of preliminary data appears to suggest that if administered in a dose-titrated fashion, ruxolitinib can be used safely in a clinical practice setting. Additionally, patients most likely to benefit from ruxolitinib treatment are those with moderate to severe constitutional symptoms or splenomegaly. Future studies are ongoing in applying ruxolitinib to other hematologic and solid tumor malignancies. More clinical experience is recommended before the utility of this medication in a routine clinical practice setting can be fully determined. [ABSTRACT FROM AUTHOR]

Background: Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17). Objective: We sought to demonstrate proof of concept in patients with stable plaque psoriasis. Methods: Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). Results: Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC50) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. Limitations: This study was limited by the relatively short study duration and small sample size. Conclusion: Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C2C12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. [ABSTRACT FROM AUTHOR]

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC0-∞) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)–6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC0-∞ by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin. [ABSTRACT FROM PUBLISHER]

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers. [ABSTRACT FROM PUBLISHER]

Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are characterized by stem cell-derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph-negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph-negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2V617F). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non-tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon-α have also shown promising results in MPNs. Cancer 2011;117:662-76. [ABSTRACT FROM AUTHOR]