Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia

Baerlocher, Gabriela M.; Leibundgut, Elisabeth Oppliger; Ottmann, Oliver G.; Spitzer, Gary; Odenike, Olatoyosi; McDevitt, Michael A.; Röth, Alexander; Daskalakis, Michael; Burington, Bart; Stuart, Monic J.; Snyder, David S.

doi:10.1056/nejmoa1503479

Cited by 179 publications

(164 citation statements)

References 25 publications

Supporting

Mentioning

157

Contrasting

Unclassified

Order By: Relevance

“…86 This study showed hematologic and molecular responses but also nonnegligible adverse events. It has been suggested that imetelstat may change the natural history of MPN, 87 but its side-effect profile appears hardly acceptable in ET patients.…”

mentioning

confidence: 57%

How I treat essential thrombocythemia

Rumi

Cazzola

2016

Blood

View full text Add to dashboard Cite

Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm that may be complicated by vascular events, including both thrombosis and bleeding. This disorder may also transform into more aggressive myeloid neoplasms, in particular into myelofibrosis. The identification of somatic mutations of JAK2, CALR, or MPL, found in about 90% of patients, has considerably improved the diagnostic approach to this disorder. Genomic profiling also holds the potential to improve prognostication and, more generally, clinical decision-making because the different driver mutations are associated with distinct clinical features. Prevention of vascular events has been so far the main objective of therapy, and continues to be extremely important in the management of patients with ET. Low-dose aspirin and cytoreductive drugs can be administered to this purpose, with cytoreductive treatment being primarily given to patients at high risk of vascular complications. Currently used cytoreductive drugs include hydroxyurea, mainly used in older patients, and interferon α, primarily given to younger patients. There is a need for disease-modifying drugs that can eradicate clonal hematopoiesis and/or prevent progression to more aggressive myeloid neoplasms, especially in younger patients. In this article, we use a case-based discussion format to illustrate our approach to diagnosis and treatment of ET.

show abstract

mentioning

confidence: 57%

How I treat essential thrombocythemia

Rumi

Cazzola

2016

Blood

View full text Add to dashboard Cite

show abstract

“…In terms of treatment, the limitation of JAK inhibitors to disease palliation is now well recognized and there is a dire need for disease-modifying drugs. In this regard, two papers on the telomerase inhibitor imetelstat were recently published in the New England Journal of Hematology and showed a potential diseasemodifying activity through the induction of clinical, histological and molecular remissions in both ET and PMF [150,151]. In PMF [151], imetelstat produced complete or partial remissions in 21% of 33 patients with high-or intermediate-2-risk disease.…”

Section: The Futurementioning

confidence: 99%

“…Response appeared to be positively influenced by the presence of JAK2 mutation (27% vs. 0%) and absence of ASXL1 mutation (32% vs. 0%); similarly, the rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without such mutations. In ET [150], 18 patients were treated with imetelstat and all 18 achieved hematologic response and 16 complete hematologic response. In addition, molecular responses were seen in 7 of 8 JAK2-mutated ET patients and reduction in mutant allele burden was also seen in CALR and MPL mutated patients.…”

Section: The Futurementioning

confidence: 99%

See 1 more Smart Citation

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

View full text Add to dashboard Cite

Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

show abstract

“…[9][10][11] Trials are now ongoing in myeloproliferative disease with promising results in myelofibrosis and essential thrombocythemia. 12,13 hTERT is the catalytic subunit of the telomerase holoenzyme. In addition, hTERT has various telomere-independent functions, including enhancement of cellular proliferation, initiation of the DNA damage response through changes in chromatin structure, 14 and inhibition of apoptosis by upregulation of BCL2 expression.…”

Section: Introductionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

View full text Add to dashboard Cite

Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

show abstract

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia

Cited by 179 publications

References 25 publications

How I treat essential thrombocythemia

How I treat essential thrombocythemia

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

Contact Info

Product

Resources

About