imetelstat and Myeloproliferative-Disorders

Hyperactive signaling of the Janus-Associated Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is central to the pathogenesis of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPN), i.e., polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) which are characterized by inherent biological and clinical heterogeneity. Patients with MPNs suffer from substantial symptom burden and curtailed longevity due to thrombohemorrhagic complications or progression to myelofibrosis or acute myeloid leukemia. Therefore, the management strategies focus on thrombosis risk mitigation in PV/ET, alleviation of symptom burden and improvement in cytopenias and red blood cell transfusion requirements, and disease course alteration in PMF. The United States Food and Drug Administration's (USFDA) approval of two JAK inhibitors (ruxolitinib, fedratinib) has transformed the therapeutic landscape of MPNs in assuaging the need for frequent therapeutic phlebotomy (PV) and reduction in spleen and symptom burden (PV and PMF). Despite improving biological understanding of these complex clonal hematopoietic stem/progenitor cell neoplasms, none of the currently available therapies appear to modify the proclivity of the disease per se, thereby remaining an urgent unmet clinical need and an ongoing area of intense clinical investigation. This review will highlight the evolving targeted therapeutic agents that are in early- and late-stage MPN clinical development.

Topics: Animals; Antineoplastic Agents; Bridged-Ring Compounds; Cancer Vaccines; Humans; Janus Kinases; Myeloproliferative Disorders; Nitriles; Oligonucleotides; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Sulfonamides; Thrombocythemia, Essential

Topics: Animals; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Humans; Indoles; Myeloproliferative Disorders; Niacinamide; Oligonucleotides; Telomerase

Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene

Topics: Cytokines; Enzyme Inhibitors; HEK293 Cells; Humans; Membrane Glycoproteins; Myeloproliferative Disorders; NF-kappa B; Oligonucleotides; Signal Transduction; Telomerase; Thrombocytopenia; Toll-Like Receptors

All current treatment strategies for myeloproliferative neoplasms (MPN) patients with the exception of allogeneic stem cell transplant (ASCT) are continuously administered. Treatment approaches that reduce the degree of minimal residual disease (MRD) might permit possible drug holidays or potential cures.. Authors discuss the presently available agents and those that are under clinical development that might induce a state of MRD and can be administered intermittently. Data extracted from a comprehensive search of peer review literature performed in Pubmed as well as information presented in scientific meetings.. Currently, the only potential curative treatment for MPN is ASCT. ASCT requires a period of intense treatment but ultimately allows the patient to enjoy a period independent of continued treatment. There is evidence that intermittent use of busulfan or prolonged use of IFN-α can induce hematological remissions that are sustained for prolonged periods of time, allowing for drug holidays. The experimental drug Imetelstat is a promising drug that has been reported to prolong survival in very high-risk myelofibrosis patients after a limited period of time of administration. New experimental drugs and drug combinations that target the malignant clone and/or microenvironmental abnormalities have the potential to eliminate MRD, which might allow for drug holidays and reduction in the duration of therapy.

Topics: Allografts; Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Drug Administration Schedule; Drug Therapy, Combination; Drugs, Investigational; Duration of Therapy; Hematinics; Hematopoietic Stem Cell Transplantation; Hormones; Humans; Immunologic Factors; Interferon-alpha; Myeloproliferative Disorders; Neoplasm, Residual; Oligonucleotides; Phlebotomy; Quality of Life; Telomerase; Treatment Outcome

Topics: Antineoplastic Agents; Hematologic Neoplasms; Homeodomain Proteins; Humans; Interferon-alpha; Myeloproliferative Disorders; Nitriles; Oligonucleotides; Pain Management; Polyethylene Glycols; Pyrazoles; Pyrimidines; Recombinant Proteins; Serum Amyloid P-Component