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    • The other advanced phase JAK inhibitor pacritinib

    2018-10-23

    The other advanced phase JAK inhibitor, pacritinib, is a dual JAK2/FLT3 kinase inhibitor that has been shown to reduce splenomegaly and MF-related symptoms (Komrokji et al., 2015). A unique aspect of this inhibitor is the potential lack of significant anemia and thrombocytopenia noted with other JAK inhibitors. In a phase 2 study, in which 35 intermediate/high-risk MF patients were enrolled, 40% had CMX001 <10g/dL and 43% had platelets <100,000×109/L at entry (Komrokji et al., 2015). The percentage change in hemoglobin measurements at each study visit relative to the baseline visit stayed within a median of 6%. Platelet count measurements decreased by a median of 12% at week 12 and 17.6% at week 24, but these levels remained stable through week 60. Grade 1/2 diarrhea and nausea were the most common adverse events (AEs). Two ongoing phases 3 trials are comparing pacritinib to best available therapy (NCT01773187 and NCT02055781).
    Novel Treatment Strategies: Beyond JAK Inhibitor Monotherapy
    Interferon Interferon (IFN) alpha, a cytokine with antiviral, immunomodulatory, and growth inhibitory properties, has been of interest for the treatment of MPNs for decades (Kiladjian et al., 2008a, 2008b). Standard IFN alpha has been associated with hematologic response rates close to 80% for PV and ET, but its use is limited by toxicities, such as cytopenias, flu-like symptoms, and fatigue, leading to treatment discontinuation in up to 20% of patients. In a multicenter phase 2 study of pegylated (peg)-IFN alpha-2a involving 40 PV patients, there was a 95% complete hematologic response rate among the evaluable patients at 12months and a 90% molecular response, as assessed by JAK2 V617F allele percentage, which declined from 45% at baseline to 3% after 36months (Kiladjian et al., 2008a, 2008b). In another phase 2 study of peg-IFN, complete hematologic responses were achieved in 76% and 77% of patients with PV and ET, respectively, along with complete molecular response in 18% and 17% (Quintás-Cardama et al., 2013). However, twenty percent of the patients in this study discontinued the treatment because of drug-related toxicity. In addition to reductions in JAK2 V617F allele burden, CALR mutant molecular responses have also been noted among ET patients treated with peg-IFN (Verger et al., 2015). The next-generation, mono-pegylated IFN alpha-2b isoform, ropeginterferon alpha-2b, administered every 2weeks, was assessed in a phase 1/2 study involving 51 PV patients, yielding an overall response rate of 90% and a complete response rate of 47% (Gisslinger et al., 2015). The complete and partial molecular response rates were 47% and 43%, respectively. Overall, interferon treatment has major efficacy in the treatment of PV and ET, while its efficacy in MF is more limited and its role in MF management not well-defined (Ianotto et al., 2013).
    Epigenetic Therapies As mentioned, a number of recurrent somatic mutations observed in MPN are involved with epigenetic processes and include the following: TET2, involved with methylcytosine residue hydroxylation (Delhommeau et al., 2009); DNMT3A, a cytosine methyltransferase (Abdel-Wahab et al., 2011b); IDH1/2, oxidoreductases leading to 2-hydroxyglutarate production that inhibits alpha-ketoglutarate-dependent enzymes such as TET2 (Tefferi et al., 2012); ASXL1, involved with HOX gene regulation via Polycomb repressive complex 2 (PRC2)-mediated histone methylation (Abdel-Wahab et al., 2012); and EZH2, a histone methyltransferase component of PRC2 (Abdel-Wahab et al., 2011a). Of note, JAK2 functions as an epigenetic modifier by affecting histone posttranslational modifications. Genome-wide methylation studies have revealed hyper- and hypomethylation in promoter regions and in non-CpG island loci among MPN samples, as compared with healthy controls, with differences also noted between PMF and PV/ET samples (Nischal et al., 2013). Particular methylomic signatures were associated with the presence of ASXL1 and TET2 mutations. Also supporting the role of epigenetic aberration in the pathogenesis of MPNs, histone deacetylase (HDAC) activity has been observed to be elevated in PMF patients as compared with other MPN patients and healthy volunteers, with HDAC levels correlating to degree of splenomegaly (Wang et al., 2008). Global gene expression profiling of blood from patients with MPNs has revealed abnormalities in the expression of various HDAC genes (Skov et al., 2012).