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- Myeloproliferative neoplasms. [Journal Article]
- Clin Med 2013 Apr; 13(2):188-92.
- Population Pharmacokinetic Analysis of Orally-Administered Ruxolitinib (INCB018424 Phosphate) in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET MF). [JOURNAL ARTICLE]
- J Clin Pharmacol 2013 May 16.
Ruxolitinib is a selective inhibitor of Janus kinase 1 and 2, which is approved to treat intermediate or high-risk myelofibrosis. The population pharmacokinetics for ruxolitinib were characterized by a modeling dataset of 272 subjects from a Phase 2 and a Phase 3 study and validated by an external validation dataset of 142 subjects from a second Phase 3 study. The PK of ruxolitinib was adequately described by a two-compartment disposition model with first-order absorption and linear elimination. All model parameters were estimated with good precision. Gender and body weight were identified as covariates for oral clearance (CL/F) and volume of distribution for central compartment (Vc/F), respectively. Apparent oral clearance was 22.1 and 17.7 L/h for a typical male and female subject, respectively, with 39.1% unexplained inter-individual variability (IIV). The typical Vc /F for a subject with a median weight of 72.9 kg was estimated to be 58.6 L, with 28% unexplained IIV. The model predictive performance was validated by visual predictive check (VPC) and the external validation dataset. This analysis suggests that effects of gender and body weight on ruxolitinib PK are not clinically significant and hence no dose adjustment is needed based on gender and weight.
- A rare der(Y)t(Y;1)(q12;q12) in a patient with post-polycythemic myelofibrosis: a case report. [Journal Article]
- Am J Blood Res 2013; 3(2):186-90.
We describe a case of post-polycythemic myelofibrosis harboring der(Y)t(Y;1)(q12;q12). The patient was a 69-year-old man and was initially diagnosed with polycythemia vera. During the clinical course of his condition, the polycythemia developed into myelofibrosis. Chromosome analysis detected der(Y)t(Y;1)(q12;q12). We discuss the association between der(Y)t(Y;1)(q11~12;q12~21) and tumorigenesis along with a review of literature.
- Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. [JOURNAL ARTICLE]
- Br J Haematol 2013 May 14.
Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health-related quality of life (HRQoL). Here, we report post-hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease-related symptoms and HRQoL in MF patients from the large phase 3 COMFORT-II study (N = 219). During the follow-up period of 48 weeks, HRQoL and MF-associated symptoms improved from baseline for ruxolitinib-treated patients but remained the same or worsened for best available therapy (BAT)-treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ-C30), treatment-induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT-General, FACT-Lym trial outcome index, and FACT-Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.
- Subcellular mislocalization of the transcription factor NF-E2 in erythroid cells discriminates pre-fibrotic primary myelofibrosis from essential thrombocythemia. [JOURNAL ARTICLE]
- Blood 2013 May 13.
The WHO classification of myeloproliferative neoplasms (MPN) comprises several entities including essential thrombocythemia (ET), primary myelofibrosis (PMF) and MPN,unclassifiable (MPN,U). Differential diagnosis between ET and early, pre-fibrotic PMF can be challenging but is critical as clinical course and outcome vary considerably between these entities. We have previously shown that the transcription factor NF-E2 is aberrantly expressed in MPN patients. Here we demonstrate that NF-E2 is mis-localized in PMF cells and that aberrant NF-E2 localization discriminates statistically highly significantly between ET and PMF. A threshold of 20% nuclear NF-E2 staining was cross-validated by ".682+ bootstrapping". Moreover, this cut-off correctly classifies diagnostic bone marrow biopsies of MPN,U patients specified upon follow-up as ET or PMF with 92% accuracy. Because inter-observer concordance between independent pathologists was high (Spearman's rank correlation coefficient: 0.727), we propose that quantitative NF-E2 immunohistochemistry represents a diagnostic tool which can reliably support a differential diagnosis between ET and PMF.
- Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. [JOURNAL ARTICLE]
- Int J Hematol 2013 May 14.
The discovery of activating mutations in JAK2 and MPL in a majority of patients with myeloproliferative neoplasms (MPN) has led to the rapid clinical development of several JAK kinase inhibitors. Of these, the JAK1/2 inhibitor, ruxolitinib (INCB018424, Incyte Corporation) was recently approved for the treatment of patients with myelofibrosis (MF). JAK inhibitors have effectively reduced splenomegaly and high cytokine levels in patients leading to improvements in quality of life. However, they have not been successful in eliminating the mutant clone in a majority of patients. In vitro studies using saturation mutagenesis screens have revealed several mutations in JAK2 that confer resistance to JAK inhibitors. Nevertheless, these mutations have not been identified so far in JAK inhibitor-treated patients. A recent study from our laboratory demonstrated that chronic JAK kinase inhibition leads to JAK inhibitor persistence via transphosphorylation of JAK2 through other JAK kinase family members. This phenomenon is seen in cell lines, mouse models and patient samples. The JAK inhibitor persistent cells, however, still remain JAK2 dependent and therefore combination therapies that target JAK2 and other components of the JAK-STAT pathway along with JAK inhibitors may provide additional benefits and improve clinical outcomes in these patients.
- Pharmacological management of essential thrombocythemia. [JOURNAL ARTICLE]
- Expert Opin Pharmacother 2013 May 14.
Introduction: Two factors have deeply influenced the area of essential thrombocythemia (ET). A gain-of-function mutation in the pseudokinase region of the JAK2 gene, which partly explains the pathophysiology of myeloproliferative neoplasms (MPNs), was discovered in 2005 and is present in 50 - 60% of ET patients. Furthermore, the 2008 WHO MPN classification outlined criteria for the separation of ET and early or prefibrotic primary myelofibrosis (PMF). However, these and other new findings have not yet changed the pharmacotherapy of ET, which is based on risk stratification for thrombohemorrhagic risk and aims to reduce thrombosis and bleeding. Areas covered: Studies on the basis for and the validation of the WHO classification as well as studies on possible new risk factors are covered. The most important drugs for ET treatment and consensus recommendations for management of ET are also presented. Expert opinion: The new WHO classification should be used for both ET studies and clinical practice, since true ET has a different prognosis than early PMF. The management of patients should be based on risk stratification. Age > 60 years or previous throbosis (high risk) and platelet counts > 1500 × 10(9)/l warrant cytoreductive treatment, and high risk patients and selected low risk patients should be given anti-aggregation therapy.
- Laboratory Detection of JAK2 (V617F) in Human Myeloproliferative Neoplasms. [Journal Article]
- Methods Mol Biol 2013.:41-57.
Recently, a point mutation in the JAK2 gene, JAK2 (V617F) , was discovered in several myeloid proliferative neoplasms including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Demonstration of the mutation and other similar mutations has now become one of the major criteria in the diagnosis of these neoplasms in the revised World Health Organization Classification of Tumors of Hematopoietic Tissues. In this chapter, we compared the advantages and disadvantages of five commonly used methods for the detection of JAK2 (V617F) . We explained, based on the current literature, why analytic sensitivity of the methodology is of particular importance for the detection of JAK2 (V617F) . A detailed laboratory procedure for the performance of an extensively optimized ARMS-PCR assay was presented. The assay shows distinct patterns for normal, mutant, and mixed genotypes. Diagnostically, it is highly sensitive, highly specific, and simple to perform with no need for any specialized equipment other than thermocyclers.
- Reduced Toxicity Conditioning and Allogeneic Stem Cell Transplantation in Adults using Fludarabine, BCNU, Melphalan, and Antithymocyte Globulin (FBM-A): Outcomes depend on Disease Risk Index but not Age, Comorbidity Score, Donor Type, or HLA Mismatch. [JOURNAL ARTICLE]
- Biol Blood Marrow Transplant 2013 May 7.
Although reduced intensity conditioning (RIC) has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pre-transplant patient- and/or disease-specific risk factors. We report here results in 100 adults age 18 - 69 with high-risk hematologic malignancy who received conditioning with fludarabine, BCNU, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. . Median age was 56, and patients were ineligible for standard myeloablative conditioning due to age, organ dysfunction, or prior autologous HCT. Patients were transplanted for myeloid (AML, n=40; MDS, n=24, myelofibrosis, n=13, other myeloid, n=2) or lymphoid (ALL, n=8; NHL, n=8, Hodgkin lymphoma, n=4, CLL, n=1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at one or 2 HLA loci in 33); grafts were PBSCs in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67; DRI Low/Int), and 32 as high (n = 28) or very high risk (n = 4; DRI High/VH). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the Low/Int risk group is 80%, compared to 66% in the High/VH group (P = .11). Two-year cumulative incidence of relapse and non-relapse mortality in the Low/Int group are 9.9% and 15%, vs. 25% and 19% in the High/VH group (respective P values 0.07 and 0.81). The cumulative incidence of acute GVHD grades III-IV at 100 days was 8.1%, and the incidence of NIH-defined moderate-to-severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, HCT-CI score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low, intermediate, or high risk scores according to the DRI.